Background: Modifiable risk factors for cardiovascular disease (CVD) account for much of the variability in CVD outcomes and are also related to psychosocial variables. There is evidence that depression can undermine the treatment and advance the progression of CVD risk factors, suggesting that CVD risk factor relationships with CVD events may differ among those with depression. Methods: This study tracked CVD events and mortality over a median of 5.9 years among a prospective cohort of 620 women (mean age 59.6 years [11.6]) completing a diagnostic protocol including coronary angiography and CVD risk factor assessment. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The study outcome was combined cardiovascular mortality and events. Results: Over the follow-up interval, 16.1% of the sample experienced one or more of the cardiovascular outcomes. In separate Cox regression models adjusting for age, education history, ethnicity, and coronary angiogram scores, we observed statistically significant CVD risk factor × BDI score interactions for diabetes, smoking, and waist-hip ratio factors. Simple effect analyses indicated that diabetes and smoking status were more strongly associated with cardiovascular outcomes among participants with lower BDI scores, whereas waist-hip ratio values predicted outcomes only among those with higher BDI scores. Conclusions: These results suggest that the relationship between modifiable CVD risk factors and CVD outcomes may vary with depression status in clinical samples of women. This evidence augments prior research by demonstrating that depression may influence CVD risk jointly with or independent of CVD risk factors. It also provides further support for the inclusion of depression assessment in cardiovascular clinic settings. © 2012, Mary Ann Liebert, Inc.