The purpose of the study was to test relationships between psychosocial factors and alcohol and illicit drug use among high-risk youth living with HIV (YLH). One hundred eighty-six high-risk youth with HIV (defined as those with a substance use problem, sexual risk problem, or medication adherence problem) were enrolled across five cities (ages 16-24). Alcohol and illicit drug use were measured with the alcohol, smoking, and substance involvement screening test and a timeline follow-back interview. Questionnaires assessed constructs from the adapted Transtheoretical Model (TTM) including a continuous measure of motivational readiness in response to criticisms of the stage component. Path analysis was utilized to fit cross-sectional data collected via computer assisted personal interviewing (baseline data from intervention study). Separate models were fit for each commonly used substance. In the previous month, 47% used alcohol, 37% used cannabis, and 9% used other illicit drugs. Path models fit the data well and accounted for 30% of the variance in alcohol use and 47% in cannabis use. Higher self-efficacy predicted lower alcohol and cannabis use, but motivational readiness was only directly related to cannabis use. A reduction in pros of substance use was indirectly related to use. Social support and psychological distress were associated with TTM constructs. Interventions focusing on improving motivation and self-efficacy for healthy behaviors may reduce substance use in YLH.