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Background: Depression with pain comorbidity (DPC) has not been clearly defined among HIV positive patients in sub-Saharan Africa. It still remains a challenge despite many studies in Africa documenting a high prevalence of pain and depression among people living with HIV/AIDS. Both are associated with a grave impact on the health related outcomes in this pandemic. This study aimed at determining the prevalence, factors associated and effect on quality of life of DPC among HIV positive patients.Methods: In a cross-sectional survey, 345 HIV positive patients were enrolled into the study. Using a pre-tested standardised questionnaire the presence of DPC was assessed after a written informed consent. The associations between DPC, quality of life, depression history, severity, and cognition were determined. A p-value of <0.05 was considered to be significant.Results: Among people living with HIV/AIDS (PLWHA), the prevalence of DPC was about 5%. PLWHA with DPC were more likely to perceive their overall quality of life as poor and scored poorly in all the domains on the WHOQOL-BREF. They were also more likely to have more severe forms of depression and recurrent episodes of depression.Conclusions: DPC is common, under diagnosed and undertreated in PLWHA in Uganda. Depression and pain screening as well as appropriate access to care for DPC have potential to improve quality of life and health outcomes. This calls for the integration and training of mental health services into HIV/AIDS care and future efforts by policy makers and HIV caregivers to address this treatment gap to advance the care of people living with HIV in Uganda. [ABSTRACT FROM AUTHOR]