Background: Depression may lead to weight gain and obesity. Few prospective studies have examined the relation of depression to weight gain and obesity among African-American women, though obesity disproportionately affects this population. Methods: We assessed the association of depressive symptoms with weight gain and risk of obesity in the Black Women’s Health Study (BWHS), an ongoing prospective cohort study initiated in 1995. We included 22,240 non-obese women who completed the Center for Epidemiologic Studies Depression Scale (CES-D) in 1999 and followed them for weight change through 2013. We categorized depressive symptoms into CES-D <16, 16-22, 23-32, and ≥33; values of ≥16 have a moderate to high sensitivity for major depression. We used generalized estimating equations to estimate mean weight change in relation to symptoms of depression and Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between depressive symptoms and incident obesity. The basic multivariate model was adjusted for age, time period, height, antidepressants use, education, and marital status. To this model, we added lifestyle factors (dietary patterns, energy intake, exercise, hours of TV watching, smoking, and alcohol drinking) to assess whether the association of depressive symptoms with weight gain and obesity was independent of these factors. Results: Relative to CES-D <16, mean weight-gain difference (95% CI) during 14 years of follow-up for CES-D 16-22, 23-32, and ≥33 were 0.88 kg (0.40, 1.36), 0.28 kg (-0.35, 0.90), and 1.15 kg (0.07, 2.22) (P-trend = 0.001), respectively. After adjustment for lifestyle factors, the respective differences decreased to 0.80 kg (0.32, 1.27), 0.15 kg (-0.48, 0.78), and 1.01 kg (-0.06, 2.09) (P-trend = 0.008). Participants with CES-D ≥16 had a mean weight difference of 0.73 kg (0.34, 1.12) in the basic multivariate model, and 0.62 kg (0.24, 1.01) in the lifestyle-adjusted model compared to subjects with CES-D <16. Regarding incident obesity, in the basic multivariate model, HRs (95% CI) of obesity for CES-D 16-22, 23-32, and ≥33 were 1.17 (1.10, 1.25), 1.07 (0.98, 1.16), and 1.21 (1.08, 1.37) (P-trend <0.0001), respectively. Corresponding HRs decreased to 1.14 (1.07, 1.22), 1.03 (0.95, 1.12), and 1.16 (1.03, 1.31) (P-trend = 0.001) after adjustment for dietary and physical activity covariates. Women with CES-D ≥16 had a HR of obesity equal to 1.14 (1.08, 1.20) in the basic multivariate model, and 1.11 (1.05, 1.17) in the lifestyle-adjusted model. Conclusions: Our results suggest a modest association of symptoms of depression with higher weight gain and risk of obesity. The association was attenuated but persisted after successive adjustment for lifestyle factors, suggesting an independent effect of depression on weight gain and obesity.