The COVID-19 pandemic poses a risk to mental health and may disproportionately affect people living with HIV (PLWH). This study examined the interaction of social support and resilient coping in predicting depressive symptoms among PLWH. PLWH residing in Buenos Aires, Argentina and in Miami, Florida (US) were asked to complete an anonymous survey on the impact of COVID-19. Statistical analysis included ordinary least squares regression. A total of 1,554 participants were included. Mean age was 47.30 years; 63.70% were men. A test of three-way interaction of social support × resilient coping × study site indicated differences by site (b = -0.63, p = 0.04, 95%CI [-1.24, -0.02]). In Argentina, higher levels of social support and resilient coping were associated with lower depressive symptoms. Lower levels of social support and resilient coping were associated with higher depressive symptoms. The impact of COVID-19 on mental health illustrates the need for developing innovative strategies to support resilience and to enhance coping with stress and adversity among PLWH.