INTRODUCTION: With the availability of antiretroviral therapy (ART) and primary general care for people living with HIV (PLHIV) in resource limited settings, PLHIV are living longer, and HIV has been transformed into a chronic illness. People are diagnosed and started on treatment when they are relatively well. Although ART results in clinical improvement, the ultimate goal of treatment is full physical functioning and general well-being, with a focus on quality of life rather than clinical outcomes. However, there has been little research on the relationship of specific factors to quality of life in PLHIV. The objective of this study was to investigate factors associated with quality of life among PLHIV in Uganda receiving basic care and those on ART. METHODS: We enrolled 1274 patients attending an HIV outpatient clinic into a prospective cohort study. Of these, 640 received ART. All were followed up at 3 and 6 months. Health related quality of life was assessed with the MOS-HIV Health Survey and the Global Person Generated Index (GPGI). Multivariate linear regression and logistic regression with generalized estimating equations were used to examine the relationship of social behavioral and disease factors with Physical Health Summary (PHS) score, Mental Health Summary (MHS) score, and GPGI. RESULTS: Among PLHIV receiving basic care, PHS was associated with: sex (p=0.045) - females had lower PHS; age in years at enrollment (p=0.0001) - older patients had lower PHS; and depression (p<0.001) - depressed patients had lower PHS. MHS was only associated with opportunistic infection (p=0.01) - presence of an opportunistic infection was associated with lower MHS. For the GPG the associated variables were age (p=0.03) - older patients had lower GPGI; education (p=0.01) - higher education associated with higher GPGI; and depression - patients with depression had a lower GPGI (p<0.001). Among patients on ART, PHS was associated with: study visit (p=0.01), with increase in time there was better PHS, and this also improved with increase in education level (p=0.002). Patients with WHO disease stage 3&4 had a lower PHS compared to patients at stage 1&2 (p=0.006), and depressed patients had lower PHS (p<0.001). MHS improved from baseline to six month study visit (p<0.001), and females had lower MHS compared to males (p=0.01). GPGI was associated with higher income (p=0.04), alcohol use was associated with lower GPGI (p=0.004), and depressed patients had a lower GPGI (p<0.001). CONCLUSION: Quality of life improved over time for PLHIV on ART. Regardless of treatment status, PLHIV with depression or low education level and female gender were at risk of having a poor quality of life. Clinicians and policy makers should be aware of these findings, and address them to improve quality of life for PLHIV.