The study explored barriers to antiretroviral medication adherence in perinatally and behaviorally HIV infected adolescents and young adults in a cross-sectional, multisite sample. The study included a subset of a convenience sample from a cross-sectional analysis. Participants were youth with HIV ages 12-24 who were prescribed HIV medication and reported missing medication in the past 7 days (n = 484, 28.4 % of protocol sample). The top barriers were similar for perinatally and behaviorally infected youth, but perinatally infected youth reported significantly more barriers. Forgetting, not feeling like taking medication and not wanting to be reminded of HIV infection were the most common barriers reported. Number of barriers was significantly correlated with percent of doses missed, viral load, and psychological distress for perinatally infected youth and with doses missed, psychological distress, and substance use for behaviorally infected youth. Interventions to improve adherence to HIV medications should not only address forgetfulness and choosing not to take medications, but also consider route of infection.