Medication adherence among HIV-infected individuals is critical to limit disease progression and onward transmission. Evidence indicates that among youth living with HIV (YLH), adherence is suboptimal and related to co-morbid psychosocial conditions. Cross-sectional data from 212 YLH, ages 16-29, collected between 2011-2014 in Chicago were analyzed to assess the relationship of multiple psychosocial conditions (e.g., depressive symptoms, anxiety symptoms, moderate/heavy marijuana use, moderate/heavy alcohol use, HIV-related stigma) to ART adherence (i.e., a "syndemic.") Adherence was regressed on an index of increasing numbers of psychosocial conditions, controlling for demographic and treatment factors as well as enrollment site. The mean age of participants was 24, 89% were male, 87% black, and 91% behaviorally infected. Psychosocial conditions were prevalent, including 38% and 34% with high depressive and anxiety symptoms, respectively, 54% and 25% with a moderate/high level of marijuana and alcohol use, respectively, and 46% reporting high HIV-related stigma. In regression analysis, the likelihood of ART adherence decreased with the number of syndemic conditions (linear dose response, p = 0.02) as did the odds of viral load suppression (p = 0.008). Interventions to address these conditions in concert with biomedical treatment as prevention for YLH are needed.