ABSTRACTStudies exploring gender differences in health-related quality of life (HRQOL) of people living with HIV/AIDS (PLWHA) are scarce and contradictory. This study evaluated gender differences in HRQOL of 744 PLWHA with median (IQR) age 44 (37–48) years and HIV infection diagnosed 12 (5–20) years earlier. Results showed important differences between genders (p < .05). Better male physical health was related to being employed, not having economic worries, not receiving psychological support, not having injected drugs in past, low negative mood HIV-related, low HIV illness representation and internalized stigma, and high body image satisfaction and health behavior. For women, variables were fewer years since HIV diagnosis and low enacted stigma-personal experience of rejection. Mentally, variables in men were being employed, not having injected drugs, having a stable partner, high health behavior, use of problem-solving coping, personal autonomy and personal meaning. In women, better mental health was related to high CD4 cells, self-esteem and body image satisfaction, and negative mood HIV-related. Men and women coincided in absence of past opportunistic infections being related to better physical and mental health, and absence of side effects for physical health and low HIV-related stress and HIV illness representation for mental health. Our results highlight the need for detailed study of gender differences that identify the bio-psycho-socio inequalities that affect HRQOL.