<p><b>BACKGROUND: </b>The burden of depression among Hispanics/Latinos indicates the need to identify factors related to depressive symptoms. This paper examines the relationship of physical activity (PA) and sedentary behavior (SB) with depressive symptoms in Hispanic/Latinos.</p><p><b>METHODS: </b>The Hispanic Community Health Study / Study of Latinos (HCHS/SOL) is a population-based, cohort study of Hispanic/Latinos in 4 United States metropolitan areas. Objectively measured PA was coded into: sedentary behavior (SB), light-intensity (LPA), moderate-intensity (MPA), and vigorous-intensity (VPA); and the Center for Epidemiological Studies Depression Scale-10 assessed depressive symptoms. Multiple regression analysis utilizing isotemporal substitution, adjusted for relevant covariates, examined PA as predictors of depressive symptoms.</p><p><b>RESULTS: </b>Substitution of 1 hour of SB with VPA resulted in a significant decrease in depressive symptoms (β = -1.215, P = .021). Similar decreases were observed when VPA replaced LPA (β = -1.212, P = .021) and MPA (β = -1.50 P = .034). MPA and LPA were not associated with lower depressive symptoms.</p><p><b>CONCLUSIONS: </b>Previous research has focused on the relationship of MVPA on depressive symptoms. Our results suggest these constructs should be examined separately as they may have unique relationships with depressive symptoms. The association of SB with greater depressive symptoms confirms previous reports.</p>