Latinos, and Puerto Ricans in particular, have been disproportionately impacted by HIV/AIDS. Severe mental illness (SMI) is associated with an increase in HIV risk. Relatively little research has focused on the role of SMI among Puerto Rican injection drug users (IDUs) and non-IDUs in susceptibility to and transmission of HIV and there are few published reports on HIV risk among Latina SMI. We conducted a longitudinal mixed methods study with 53 Puerto Rican women with schizophrenia, bipolar disorder, or major depression to examine the cultural context of HIV risk and HIV knowledge, beliefs, and behaviors among a larger study with Puerto Rican and Mexican women with serious mental illness (SMI). There was a high prevalence of past and current substance use and a high prevalence of substance use-associated HIV risk behaviors, such as unprotected sexual relations with an IDU. The violence associated with substance use frequently increased participants’ HIV risk. Choice of substance of abuse depended on cost, availability, and use within the individual participant’s network. Participants attributed their substance use to the need to relieve symptoms associated with their mental illness, ameliorate unpleasant feelings, and deaden emotional pain. HIV prevention interventions for poorer Puerto Rican women with SMI must target the individuals themselves and others within their networks if the women are to be supported in their efforts to reduce substance use-related risk. The content of any intervention must address past and current trauma and its relationship to substance use and HIV risk, as well as strategies to prevent HIV transmission.