We examined whether social support moderated communication and self-management, and tested whether self-management mediated communication, instrumental and emotional social support (ISS, ESS), and health-related quality of life (HRQOL) in Korean people living with HIV (PLWH). A cross-sectional research design using a self-reported survey questionnaire was conducted. Data for 205 PLWH were collected at the outpatient divisions of seven hospitals. HRQOL was positively associated with communication, ISS, ESS, and self-management. ESS moderated the relationship between communication and self-management through a significant interaction with communication. Johnson-Neyman analysis indicated that the interaction effect of ESS was significant at the range from 4 to 14.4. However, the ISS did not moderate the relationship between communication and self-management. Self-management mediated the relationship between communication, ESS, and HRQOL. The findings suggest that nursing interventions should be focused on providing interactive communication and ESS to improve self-management and HRQOL of PLWH.