There has recently been growing attention and concern in the U.S. on the detrimental drug use and related health conditions impacting diverse sexual minority populations. While some evidence indicates that bisexual women are at increased risk of substance use, little attention has been given to disadvantaged and racial/ethnic minority bisexual women, who are particularly vulnerable to a complexity of stressors and risk. Using data from a 15-year longitudinal study in San Antonio, Texas, the current study examines drug use, incarceration histories, stressful life events, and infections among 206 young adult Mexican-American women who report engaging in sex with both men and women (WSWM) (n = 61) and those indicating having exclusively male sex partners (WSM) (n = 145). A bivariate analysis finds that WSWM experienced more frequent (p = 0.001) and longer total time incarcerated (p = 0.001), as well as exposure to more stressful life events (p = 0.003). WSWM also have higher rates of past 30 day injection drug use (p = 0.026) and related Hepatitis C Virus (HCV) infection (p = 0.001), as well as greater symptomatology associated with depression (p = 0.014), PTSD (p = 0.005), and suicidal ideation (p = 0.036). Findings indicate a significantly elevated risk profile for socio-economically marginalized WSWM. This knowledge is timely and central to policy discourse to develop interventions and health campaigns aimed at reducing and/or preventing further health disparities among this highly susceptible population of minority women.