Researchers exploring the health of Hispanics in South Florida utilizing a combination of qualitative and quantitative research methods have identified that substance abuse, violence, risky sexual behavior, and depression are not only conceptualized as tightly interrelated health and social problems, but also hold together in a measurement model to represent an underlying phenomenon (i.e., the Syndemic Factor). The purpose of this study is to test hypothesized relationships between cultural phenomena and the Syndemic Factor among community-dwelling Hispanic women. Standardized questionnaires assessing Acculturation, Hispanic Stress, Familism, and the Syndemic Factor were administered to a cross-sectional sample of 548 Hispanic women from South Florida. Structural equation modeling was used to analyze relationships. The model explained 61 percent of the variance in the Syndemic Factor. There was a large positive relationship between the Syndemic Factor and Hispanic Stress, and a small inverse relationship between the Syndemic Factor and Familism. Women with high Hispanic Acculturation and low U.S. Acculturation scored lower on the Syndemic Factor than Integrated/Bicultural women. Familism buffered the relationship between Hispanic Stress and the Syndemic Factor. Structural, community, family, and individual prevention strategies that address underlying conditions associated with the Syndemic Factor must be developed and formally evaluated.