Despite the scepticism of the Venetian Senate (see the previous debate), the French did pass into Italy in 1523 – to no avail – and once more in the autumn of 1524. This time, Francis I himself was at the head of a powerful army. The Imperials did not have enough forces to defend Milan, devastated as it was by the plague; accordingly, they locked themselves up in several fortified places. Francis then began to lay siege to the most important of them: that is, Pavia. Despite the coalition that Charles V had managed to make in August 1523 with Henry VIII and all the most important Italian states, not to mention the alliance with the Venetians signed the month before, the Imperials received no assistance. In addition, their poor financial resources made their position even more precarious. Being concerned about their ability to sustain themselves further, upon the arrival of a contingent of Landsknechts the imperial generals decided to launch a surprise attack upon the French camp, in coordination with the troops under siege. In the early morning of 24 February 1525, Francis's army was annihilated in a two-hour battle that would change the course of history, and the King himself was wounded and captured, while a number of French noblemen who were fighting next to him were killed. Not only did this sensational result leave Italy at the mercy of Charles V, but also it pointed at a clear French inferiority vis-à-vis Spain on a European scale – an inferiority that the French kings will be able to attenuate, but not cancel, in decades of war to come.

The news of this astonishing victory reached Charles on 10 March. According to Guicciardini, his public reaction was extremely sober:

Nor did he show ‘either in his words or gestures, any sign of immoderate gladness, or of being puffed up in mind’. The debate below took place a few days later.