Miami is a Southeastern United States (U.S.) city with high health, mental health, and economic disparities, high ethnic/racial diversity, low resources, and the highest HIV incidence and prevalence in the country. Syndemic theory proposes that multiple, psychosocial comorbidities synergistically fuel the HIV/AIDS epidemic. People living with HIV/AIDS in Miami may be particularly affected by this due to the unique socioeconomic context. From April 2017 to October 2018, 800 persons living with HIV/AIDS in a public HIV clinic in Miami completed an interviewer-administered behavioral and chart-review cross-sectional assessment to examine the prevalence and association of number of syndemics (unstable housing, low education, depression, anxiety, binge drinking, drug use, violence, HIV-related stigma) with poor ART adherence, unsuppressed HIV viral load (≥ 200 copies/mL), and biobehavioral transmission risk (condomless sex in the context of unsuppressed viral load). Overall, the sample had high prevalence of syndemics (M = 3.8), with almost everyone (99%) endorsing at least one. Each syndemic endorsed was associated with greater odds of: less than 80% ART adherence (aOR 1.64, 95% CI 1.38, 1.98); having unsuppressed viral load (aOR 1.16, 95% CI 1.01, 1.33); and engaging in condomless sex in the context of unsuppressed viral load (1.78, 95% CI 1.30, 2.46). The complex syndemic of HIV threatens to undermine the benefits of HIV care and are important to consider in comprehensive efforts to address the disproportionate burden of HIV/AIDS in the Southern U.S. Achieving the 90-90-90 UNAIDS and the recent U.S. “ending the epidemic” targets will require efforts addressing the structural, social, and other syndemic determinants of HIV treatment and prevention.