HIV-positive (HIV+) mothers and their children infected via mother-to-child transmission are at a high risk of impaired health-related quality of life (HRQoL). This risk particularly affects those living in areas with limited healthcare resources. Regrettably, this population has received insufficient attention in research and services. No intervention trial has considered the HIV+ mother–child dyad as a unit and incorporated both of them as partners in HIV management. We propose to develop brief, culturally relevant, theory-based interventions to improve the HRQoL of Chinese HIV+ mother–child dyads by addressing several key characteristics: (1) designing psychological and behavioral approaches as two active arms with potential impacts on HRQoL, (2) focusing on the mother–child dyad, (3) extending the impacts from individualistic outcomes to relationship- and family-related outcomes, (4) including cultural adaptation, and (5) encouraging sustainability. In the proposed randomized controlled trial, 198 HIV+ mother–child dyads will be assigned randomly to one of three arms: (1) resilience intervention, a psychological approach involving four sessions on stigma management, emotion management, positive coping, and social bonds; (2) adherence intervention, a behavioral approach involving four sessions on adherence information, personal motivation, social motivation, and behavioral skills based on the information–motivation–behavioral skills model; and (3) control, or treatment as usual. We will conduct a quantitative evaluation using structured measures before and after the intervention and at 1- and 3-month follow-ups. Using a mixed-method evaluation design, we will conduct semi-structured interviews to elucidate issues of the process and implementation. To examine the intervention effects on individualistic outcomes when considering mothers and children separately, we will test whether the interventions improve the mediators associated with the intervention sessions, resilience factors, self-reported adherence, and HRQoL. To examine the intervention effects at the dyadic and family levels when focusing on the mother–child dyad, we will investigate whether the resilience intervention and adherence intervention (both using the combined modality incorporating mothers and children) lead to increased dyadic coping, mother– child closeness, and family harmony. To conduct mediation analyses for elucidating the intervention effects on individualistic outcomes, we will examine whether the mediators associated with intervention sessions transmit the intervention effects on the increases in resilience factors or adherence. This trial is guided by public health priorities and will contribute to further implementation research. The findings will be helpful to promote evidence-based practice in HIV healthcare of resource-limited areas and develop culturally sensitive intervention programs among marginalized populations.