People living with HIV (PLWH) report elevated levels of posttraumatic stress disorder symptoms (PTSS) and associated comorbidities. The present study tested the efficacy of prolonged exposure (PE) at reducing PTSS, depression, negative posttraumatic cognitions, and substance use in PLWH. Participants were randomly assigned to receive PE (n = 40) or to a weekly monitoring control group (n = 25). Assessments occurred at baseline, post-intervention and 3-months post-treatment. Following the 3-month assessment, controls were offered the intervention. All PE recipients (whether originally from the PE or control group) completed a 6-month assessment. Intent-to-treat mixed model repeated measures ANOVAs were conducted through 3-months post-treatment; within group analyses were conducted through 6-months. PE recipients reported fewer PTSS and negative posttraumatic cognitions and were more likely to achieve good end-state functioning; gains were maintained at 6-months. No between-group differences emerged for substance use. Overall, results support the efficacy of PE in PLWH.