Identifying risk and protective factors associated with condomless sex among youth living with HIV is imperative for developing effective HIV prevention strategies. A cross-sectional sample of 1728 participants, 12-26 years of age, recruited from adolescent medicine clinics in 17 U.S. cities completed an audio-computer assisted self-interview with questions about their substance use, psychosocial factors, and attitudinal and behavioral factors. Guided by syndemics theory, a path analysis was used to assess the interrelations of these factors. Analyses of model fit statistics indicated statistically significant direct pathways between substance use, psychosocial factors, self-efficacy for risk-reduction, alternative risk-reduction attitudes and behaviors and condomless sex. The total indirect effect of self-efficacy for risk-reduction on condomless sex through alternative risk-reduction attitudes and behaviors was also significant. Multi-faceted, tailored interventions that address individual risk and protective factors and their combined synergistic effects are urgently needed to prevent condomless sex among this population.