As cancer survivorship increases, so does the number of patients that suffer from the late effects of radiation therapy. This includes arthrofibrosis, the development of stiff joints near the field of radiation. Previous reports have concentrated on skin fibrosis around the joint but largely ignored the deeper tissues of the joint. We hypothesized that fat, muscle, and the joint tissues themselves would play a more significant role in joint contracture after radiation than the skin surrounding the joint. To address this hypothesis, we irradiated the right hind flanks of mice with fractionated and unfractionated dose schedules, then monitored the mice for 3 months postradiotherapy. Mice were euthanized and physiological indications of arthrofibrosis including limb contracture and joint resting position were assessed. Stifle (knee) joints demonstrated significant arthrofibrosis, but none was observed in the hock (ankle) joints. During these studies, we were surprised to find that male and female mice showed a significantly different response to radiation injury. Female mice developed more injuries, had significantly worse contracture, and showed a greater difference in the expression of all markers studied. These results suggest that women undergoing radiation therapy might be at significantly greater risk for developing arthrofibrosis and may require specific adjustments to their care.