In his lecture, the pope, speaking in German, quoted an unfavorable remark about Islam made in the 14th century by Manuel II Palaiologos, a Byzantine emperor. As the English translation of the pope's lecture disseminated across the world, many Islamic politicians and religious leaders protested against what they saw as an insulting mischaracterization of Islam.

Mass street protests were mounted in many Islamic countries. In an act identified by the Pope as "their [The Muslims'] attempt to cover up the many controversial commands in the Qur'an", the Majlis-e-Shoora (Pakistani parliament) unanimously called on the Pope to retract "this objectionable statement". The pope maintained that the comment he had quoted did not reflect his own views, and he offered an apology to Muslims.

The controversial comment originally appeared in the Dialogue Held With A Certain Persian, the Worthy Mouterizes, in Anakara of Galatia, written in 1391 as an expression of the views of the Byzantine emperor Manuel II Palaiologos, one of the last Christian rulers before the Fall of Constantinople to the Muslim Ottoman Empire, on such issues as forced conversion, holy war, and the relationship between faith and reason. The passage, in the English translation published by the Vatican, is as follows:

The pope had consulted a bilingual critical edition of this dialogue in the original Greek and with French translation.

The lecture on faith and reason, with references ranging from ancient Jewish and Greek thinking to Protestant theology and modern secularity, focused mainly on Christianity and what Pope Benedict called the tendency to "exclude the question of God" from reason. Islam features in a part of the lecture: the Pope quoted a strong criticism of Islam, which he described as being of a "startling brusqueness, a brusqueness which leaves us astounded".

The author of this criticism was the Byzantine Emperor Manuel II Palaiologos (or Paleologus) in a 1391 dialogue with an "educated Persian" (who remained unnamed in the Pope's lecture), as well as observations on this argument made by Theodore Khoury, the scholar whose edition of the dialog in question the pontiff was referencing. Pope Benedict used Manuel II's argument in order to draw a distinction between a Christian view, as expressed by Manuel II, that "not acting reasonably is contrary to God's nature", and an allegedly Islamic view, as explained by Khoury, that God transcends concepts such as rationality, and his will, as Ibn Hazm stated, is not constrained by any principle, including rationality.

In part of his explication of this distinction, Pope Benedict referred to a specific aspect of Islam that Manuel II considered irrational, namely the practice of forced conversion. Specifically, the Pope (making clear that they were the Emperor's words, not his own) quoted Manuel II Palaiologos as saying: "Show me just what Muhammad brought that was new and there you will find things only bad and inhuman, such as his command to spread by the sword the faith he preached."

The pontiff was comparing apparently contradictory passages from the Qur'an, one being that "There is no compulsion in religion", the other being that it is acceptable to "spread the faith through violence". The pontiff argued the latter teaching to be unreasonable and advocated that religious conversion should take place through the use of reason. His larger point here was that, generally speaking, in Christianity, God is understood to act in accordance with reason, while in Islam, God's absolute transcendence means that "God is not bound even by his own word", and can act in ways contrary to reason, including self-contradiction. At the end of his lecture, the Pope said, "It is to the great logos, to this breadth of reason, that we invite our partners in the dialogue of cultures."

Quoted below are the three paragraphs (of sixteen total) which discuss Islam in Pope Benedict's lecture:

In the seventh conversation edited by Professor Khoury, the emperor touches on the theme of the holy war. The emperor must have known that sura 2, 256 reads: "There is no compulsion in religion". According to the experts, this is one of the suras of the early period, when Mohammed was still powerless and under threat. But naturally the emperor also knew the instructions, developed later and recorded in the Qur'an, concerning holy war. Without descending to details, such as the difference in treatment accorded to those who have the "Book" and the "infidels", he addresses his interlocutor with a startling brusqueness on the central question about the relationship between religion and violence in general, saying: "Show me just what Mohammed brought that was new, and there you will find things only evil and inhuman, such as his command to spread by the sword the faith he preached". The emperor, after having expressed himself so forcefully, goes on to explain in detail the reasons why spreading the faith through violence is something unreasonable. Violence is incompatible with the nature of God and the nature of the soul. "God", he says, "is not pleased by blood — and not acting reasonably is contrary to God's nature. Faith is born of the soul, not the body. Whoever would lead someone to faith needs the ability to speak well and to reason properly, without violence and threats… To convince a reasonable soul, one does not need a strong arm, or weapons of any kind, or any other means of threatening a person with death…