This study evaluates the efficacy of an intervention for persons living with HIV (PLH) and their family members in Thailand. A randomized controlled trial of 813 PLH and family members was carried out at four district hospitals in Thailand. Participants completed Computer Assisted Personal Interview assessments at baseline, 6, 12, 18, and 24 months. The primary outcome was quality of life (QoL); other measures included depressive symptoms and family functioning. Relative to the standard care condition, the intervention group reported significantly improved QoL at 6 months (P = 0.0014). When the intervention efficacy was stratified by baseline depressive symptoms (low vs. high), intervention efficacy was observed only among those with low depressive symptoms. Study findings suggest that the intervention was more efficacious for participants with less depressive symptoms and better family functioning. Extensive interventions may be optimal for those who have the capacity to learn the tools and skills.