In the previous debate, which took place in 1507, the Venetian senate was called upon to choose between remaining loyal to the existing alliance with the King of France or accepting the Emperor's offers. In the debate below, which takes place in 1523, the issue looks the same, yet many things had changed in the mean time. To begin with, the King of France was now Francis I. Within a few months of his crowning, in 1515, Francis took the Duchy of Milan, from which his predecessor, Louis XII, had been expelled in 1513 at the hands of the Swiss. The Venetians, who had joined the French in yet another alliance, contributed to his success, and recovered part of what they had lost in 1509. In 1516, Charles of Habsburg became king of Spain, and three years later Holy Roman Emperor, thereby concentrating under his rule an enormous mass of dominions, stretching from the Netherlands to the Kingdom of Naples. Despite this vast territorial extension, many still considered France as the more formidable power of the two: her central position, wealth, population, military capabilities and centralised government were contrasted with the dispersion of Charles V's dominions, the economic backwardness of some of them (Spain), the large autonomies of others (the Netherlands and the Holy Roman Empire) and the Lutheran movement, all of which suggested that the Emperor could have but a precarious hold on all his territories, except for the lands of the House of Habsburg. The most evident bones of contention between Francis I and Charles V, in territorial terms, included Burgundy, Navarre, Naples and Milan.

In Italy, a papal–imperial alliance was made (May 1521) for the sake of driving the French out of Milan once more and restoring the Sforza dynasty. Guicciardini, incidentally, was dispatched as a commissioner to the papal army, and witnessed the military operations that led to the liberation of Milan (except for the citadel) in November and the almost complete withdrawal of the French from Lombardy the following spring. Although Francesco Sforza was now the ruler of Milan, it was clear that his position depended on the benevolence of Charles, who, at this point, was the master of most of Italy. His eyes were now set on Venice.