Returning to France, he was sent to the Pyrenees to rescue John III of Navarre, but soon he was diverted to Thérouanne, then the last French possession in the Artois, to counter the English troops.
La Palice was sent at Calais as negotiator of the peace with Charles V. As the participants did not reach an agreement, he returned to Italy as military leader under Marshal Lautrec, commanding the French main line at the battle of Bicocca (1522), in which he was defeated by Colonna.