Transgender women (“transwomen”) face a disproportionate HIV disease burden; the odds of being HIV-positive are estimated to be 34.2 times higher for transwomen than the United States adult population. From January 1, 2005 through December 31, 2011, HIV prevention outreach encounters were conducted with 2,136 unique transwomen on the streets and at high-risk venues in Los Angeles County. The outreach encounters were comprised of a low-intensity health education and risk reduction intervention, which included referrals to needed services. The goal of the encounters was to assess the participant’s level of substance use and sexual risk behaviors to provide appropriate risk reduction strategies and supplies. The sample evidenced high rates of recent alcohol (57.7 %), marijuana (25.6 %), and methamphetamine (21.5 %) use, lifetime injection drug or illegal hormone use (66.3 %), and recent engagement in sex work (73.3 %). Multivariate logistic regression analysis revealed that recent methamphetamine (AOR = 2.09; p ≤ 0.001) and/or crack cocaine (AOR = 2.19; p = 0.010) use, injection drug/hormone use (AOR = 1.65; p ≤ 0.001), unprotected anal intercourse during sex work (AOR = 2.24; p = 0.029), and any non-Hispanic minority racial status were all associated with increased odds of reporting a HIV-positive status. The transwomen encountered via outreach exhibited many risk co-factors for HIV infection and transmission.