ABSTRACT Hispanics are disproportionately affected by substance abuse, HIV infection, intimate partner violence, and mental health conditions. To address health disparities among Hispanics and other vulnerable groups, it is necessary to understand the complex interactions between health conditions clustering together (e.g., substance abuse, intimate partner violence, and HIV) and the social ecology in which these conditions exist. A syndemic orientation, a consideration of clustering epidemics and common individual, relationship, cultural, and socioenvironmental factors linking these conditions, may be helpful in developing comprehensive models that expand our ability to understand and address health disparities. The purpose of this paper is to introduce a Syndemic Model of Substance Abuse, Intimate Partner Violence, HIV Infection, and Mental Health among Hispanics, and provide evidence from the research literature to support the central relationships and risk and protective factors (i.e., potential links between conditions) depicted by the model. The development and evaluation of interventions aimed at the prevention of substance abuse, intimate partner violence, HIV/AIDS, and mental health problems as a syndemic affecting Hispanics is urgently needed. Public health nurses can initiate this endeavor with the guidance of a Syndemic Model.