BACKGROUND: African American women have more symptoms of depressed mood than white women. Adverse neighborhood conditions may contribute to these symptoms. Although reductions in depressive symptoms with physical activity have been demonstrated in white adults, little research has examined the mental health benefits of physical activity in African American women. Further, it is unknown whether physical activity can offset the effects of living in disadvantaged neighborhoods on depressive symptoms. The purpose of this study was to examine the relationships among neighborhood characteristics, adherence to a physical activity intervention, and change over time in depressive symptoms in midlife African American women. METHODS: Two hundred seventy-eight women participated in a home-based, 24-week moderate-intensity walking intervention. Either a minimal treatment (MT) or enhanced treatment (ET) version of the intervention was randomly assigned to one of the two community health centers. Walking adherence was measured as the percentage of prescribed walks completed. Objective and perceived measures of neighborhood deterioration and crime were included. RESULTS: Adjusting for demographics, body mass index (BMI), and depressive symptoms at baseline, walking adherence and objective neighborhood deterioration were associated with significantly lower depressive symptoms, whereas perceived neighborhood deterioration was associated with significantly higher depressive symptoms at 24 weeks. CONCLUSIONS: Adherence to walking as well as aspects of the environment may influence depressive symptoms in African American women. In addition to supporting active lifestyles, improving neighborhood conditions may also promote mental health among African American women.