The authors examined depressive symptoms and prospective incidence of colorectal cancer and distal colorectal adenomas in 81,612 women without prior cancer from the Nurses' Health Study; 400 cases of colorectal cancer and 680 distal colorectal adenomas accrued between 1992 and the year 2000. Depressive symptoms were assessed in 1992 and 1996 with the five-question Mental Health Index (MHI-5), a subscale of the Short-Form 36 health status survey. Scores ranged from 0 to 100, and women with scores between 0 and 52 were defined as having significant depressive symptomatology. The authors also created four categories across the range of Mental Health Index scores: 0-52, 53-75, 76-85, and 86-100 (referent). Cox proportional hazards models were used to analyze the extent of depressive symptoms and colorectal events. Analyses were stratified by body mass index. In multivariate analyses with updated exposure, women with the highest levels of depressive symptoms had an elevated risk of incident colorectal cancer (hazard ratio = 1.43, 95% confidence interval: 0.97, 2.11) compared with women with the lowest levels of symptoms (p(trend) = 0.04). Associations appeared stronger in overweight women. However, depressive symptoms were unrelated to risk of colorectal adenomas. Associations are consistent with a possible role in late promotion of the disease.