The expedition arrived in Montréal on May 17, 1642. Maisonneuve built a fort and a central building on the site Champlain had spotted in 1611. About fifty people, including a few women, would spend their first winter in Montréal.

Maisonneuve attempted to persuade a few Amerindians on their way up- or downriver to settle near the French colony. The Iroquois, however, were establishing control over the routes used in the fur trade, and viewed the foundation of a colony in Montréal as a direct threat. They attacked the Montréalistes, killing or kidnapping some of them. This state of siege forced the settlers to live almost entirely within the fort, thus restricting agricultural development. Ville-Marie found itself on the defensive, its dream of attracting Amerindian allies fading fast.

Despite these challenges, Ville-Marie’s inhabitants managed to mount an effective defence and to benefit from breaks in the fighting. In 1645, they took advantage of a truce to build a hospital, the Hôtel-Dieu. Nonetheless, ten years after its foundation, Montréal’s population had not grown from its original fifty settlers.