Introduction: The scale-up of highly active antiretroviral therapy (HAART) has led to a significant improvement in survival of the HIV-positive patient but its effects on health-related quality of life (HRQOL) are less known and context-dependent. Our aim was to assess the temporal changes and factors associated with HRQOL among HIV-positive adults initiating HAART in Burkina Faso. Methods: HIV-positive people initiating HAART were prospectively included and followed over a one-year period in three HIV clinics of Ouagadougou. HRQOL was assessed at baseline and at each follow-up visit using physical (PHS) and mental (MHS) summary scores derived from the Medical Outcome Study 36-Item short-form health survey (MOS SF-36) questionnaire. Toxicity related to HAART modification and self-reported symptoms were recorded during follow-up visits. Determinants associated with baseline and changes in both scores over a one-year period were assessed using a mixed linear model. Results: A total of 344 patients were included. Their median age at baseline was 37 years [interquartile range (IQR) 30-44] and their median CD4 count was 181 cells/mm(3) (IQR 97-269). The mean [standard deviation (SD)] PHS score increased from 45.4 (11.1) at baseline to 60.0 (3.1) at 12 months (p < 10(-4)) and the mean (SD) MHS score from 42.2 (8.7) to 43.9 (3.4) (p<10(-2)). After one year of treatment, patients that experienced on average two symptoms during follow-up presented with significantly lower PHS (63.9) and MHS (43.8) scores compared to patients that presented no symptoms with PHS and MHS of 68.2 (p<10(-4)) and 45.3 (p<10(-3)), respectively. Discussion: The use of HAART was associated with a significant increase in both physical and mental aspects of the HRQOL over a 12-month period in this urban African population. Perceived symptoms experienced during follow-up visits were associated with a significant impairment in HRQOL. The appropriate and timely management of reported symptoms during the follow-up of HAART-treated patients is a key component to restore HRQOL.