The objective of the present study was to examine if time varying, mediating effect of physical activity plays an important role in the gender-satisfaction with life relationship. Six hundred four male and 197 female patients were included. Principal outcomes of interest were self-report satisfaction with life and physical activity at baseline, 6, 12 and 24 months. The Krull and MacKinnon procedure for hierarchical linear modeling showed that the change in physical activity mediated the gender-satisfaction with life over a 2 year period. Results from the current study suggest that increased physical activity partially explains why males report having increased well-being than females after hospitalization. This suggests that future interventions need to focus on reducing the gender disparity in physical activity to improve differences noted in satisfaction with life. If higher physical activity levels impact satisfaction with life positively, the importance of physical activity for female patients is warranted.