BACKGROUND: People living with HIV/AIDS face multiple challenges that collectively impede their adaptation outcomes. These outcomes include quality of life (QoL), acceptance of illness, mental health (including symptoms of anxiety and depression), and antiretroviral therapy (ART) adherence. While existing evidence addresses specific challenges, it often overlooks the interactions among the various problems people living with HIV/AIDS encounter. The comprehensive-task disease management framework and positive self-management framework provide a theoretical basis for understanding the adaptation process. A culturally tailored, theory-based intervention may be necessary and effective in facilitating better adaptation outcomes for people living with HIV/AIDS. OBJECTIVE: This study aimed to evaluate the effect of a hybrid intervention called AiCare (Adaptation intervention with Comprehensive-task disease management framework to achieve renormal life) on improving QoL, acceptance of illness, mental health (anxiety and depression), and ART adherence among people living with HIV/AIDS in China. METHODS: We conducted a 2-arm randomized controlled trial, recruiting 92 people living with HIV/AIDS from an HIV clinic in Hunan, China. Participants were randomly assigned in a 1:1 ratio to either the control group (receiving standard care) or the intervention group (receiving AiCare in addition to standard care). All analyses were performed from an intention-to-treat perspective. Sociodemographic and HIV-specific clinical characteristics, along with key adaptation outcomes-including QoL, acceptance of illness, mental health (anxiety and depression), and ART adherence-were assessed at baseline (T0), post intervention (T1), and 3 months post intervention (T2). We used generalized estimating equation models and difference-in-difference analysis to evaluate the interventions' effects. RESULTS: The difference-in-difference model showed that at T1, the intervention group experienced significant improvements compared to the control group. QoL increased by 6.35 (95% CI 2.62-10.93, P=.001), acceptance of illness improved by 4.49 (95% CI 2.29-6.68, P<.001), and anxiety decreased by 2.15 (95% CI 1.19-3.11; P=.01). At T2, the intervention group's improvement in QoL was not statistically significant (β 3.62, 95% CI -1.53 to 8.77; P=.17). However, acceptance of illness remained significantly improved by 3.65 (95% CI 1.22-6.08; P=.003), and anxiety decreased by 1.58 (95% CI 0.42-2.74; P=.007). No significant changes were observed in depression or ART adherence between the intervention and control groups. Feedback regarding the AiCare program indicated its acceptability and feasibility. CONCLUSIONS: The AiCare program demonstrated promising effects in improving disease adaptation outcomes among people living with HIV/AIDS, notably in enhancing QoL, fostering acceptance of illness, and mitigating anxiety symptoms. These findings underscore the hybrid program's potential clinical utility to facilitate the adaptation of people living with HIV/AIDS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400087255; https://www.chictr.org.cn/showproj.html?proj=220729.