Evidence from the literature suggests that substance abuse, violence, HIV risk, depressive symptoms, and underlying socioeconomic conditions are tied intrinsically to health disparities among Latinas. Although these health and social conditions appear to comprise a syndemic, an underlying phenomenon disproportionately accounting for the burden of disease among marginalized groups, these hypothesized relationships have not been formally tested.The aim of this study was to assess (a) if substance abuse, violence, HIV risk, and depressive symptoms comprised a syndemic and (b) if this syndemic was related to socioeconomic disadvantage among Latinas.Baseline assessment data from a randomized controlled community trial testing the efficacy of an HIV risk reduction program for adult Latinas (n = 548) were used to measure demographic variables, substance abuse, violence, risk for HIV, and depressive symptoms. Structural equation modeling was used to test a single underlying syndemic factor model and any relation to socioeconomic disadvantage.The results of this study support the idea that HIV risk, substance abuse, violence, and depressive symptoms comprise a syndemic, χ(27) = 53.26, p < .01 (relative χ = 1.97, comparative fit index = .91, root mean square error of approximation = .04). In addition, in limited accord with theory, this factor was related to 2 measures of socioeconomic disadvantage, percentage of years in the United States (b = 7.55, SE = 1.53, p < .001) and education (b = -1.98, SE = .87, p < .05).The results of this study could be used to guide public health programs and policies targeting behavioral health disparity conditions among Latinos and other vulnerable populations. Further study of the influence of gender-role expectations and community-level socioeconomic indicators may provide additional insight into this syndemic.