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African American men are disproportionately affected by, not only HIV/AIDS, but also chronic non-communicable diseases. Despite the known benefits of physical activity for reducing chronic non-communicable diseases, scant research has identified factors that may influence physical activity in this population. A growing literature centers on the syndemic theory, the notion that multiple adverse conditions interact synergistically, contributing to excess morbidity. This secondary data analysis examined two primary questions: whether syndemic conditions prospectively predicted physical activity, and whether, consistent with the syndemic theory, syndemic conditions interacted to predict physical activity. Participants were 595 African American men who have sex with men (MSM), a population underrepresented in health research, enrolled in a health-promotion intervention trial from 2008–2011. We used generalized-estimating-equations models to test the associations of syndemic conditions and resilience factors measured pre-intervention to self-reported physical activity 6 and 12 months post-intervention. As hypothesized, reporting more syndemic conditions pre-intervention predicted reporting less physical activity 6 and 12 months post-intervention, adjusting for the intervention. However, contrary to the syndemic theory, we did not find evidence for the interaction effects of syndemic conditions in predicting physical activity. Receiving high school education and having greater social network diversity predicted more physical activity whereas older age predicted less physical activity. To our knowledge, this is the first study to examine the syndemic …