Although physical activity (PA) has been inversely associated with depressive symptoms, it is not clear whether regular PA and television watching are associated with clinical depression risk. The authors conducted a prospective analysis involving 49,821 US women from the Nurses' Health Study who were free from depressive symptoms at baseline (1996). Information on PA was obtained from validated questionnaires completed in 1992, 1994, 1996, 1998, and 2000; analyses were conducted using the cumulative average of PA (minutes/day) with a 2-year latency period applied. Participants were asked about television-watching habits in 1992. Cox proportional hazards regression models adjusted for multiple risk factors were used to estimate relative risks of clinical depression (self-reported physician-diagnosed depression or use of antidepressants). During 10 years of follow-up (1996-2006), 6,505 incident cases of depression were documented. Higher levels of PA were associated with lower depression risk. The multivariate relative risk comparing the highest level of PA (≥ 90 minutes/day) with the lowest (<10 minutes/day) was 0.80 (95% confidence interval: 0.70, 0.92; P(trend) < 0.001). In contrast, the risk of depression increased with increasing television-watching time. The multivariate relative risk comparing women who spent 21 hours/week or more watching television with those who spent 0-1 hour/week was 1.13 (95% confidence interval: 1.00, 1.27; P(trend) = 0.01). Analyses simultaneously considering PA and television watching suggested that both contributed independently to depression risk.