Entering HIV care is a vulnerable time for newly diagnosed individuals often exacerbating psychosocial difficulties, which may contribute to poor health-related quality of life (HRQOL) ultimately influencing health behaviors including ART adherence, the driver of viral load suppression. Understanding HRQOL in people newly entering HIV care is critical and has the potential to guide practice and research. This exploratory cross-sectional study examined demographic, clinical, and psychosocial factors associated with limitations in four specific domains of HRQOL among persons initially entering outpatient HIV care at four sites in the United States (n = 335). In the unadjusted analysis, female gender was significantly associated with sub-optimal HRQOL with women having increased odds of reporting HRQOL challenges with pain, mood, mobility, and usual activity when compared to men. The adjusted models demonstrated attenuation of parameter estimates and loss of statistical significance for the associations with impaired HRQOL observed among women in unadjusted analyses, suggesting psychosocial factors related to HRQOL are complex and interrelated. Findings are consistent with a robust literature documenting gender-related health disparities. Programs aimed at improving HRQOL for persons initially entering HIV care are warranted generally, and specifically for women, and must address modifiable psychosocial factors via mechanisms including coping and social support.