This study assessed health-related quality of life (HRQOL) of highly active antiretroviral therapy (HAART) recipients aged 18 or older and associated factors, 2 years after HAART administration had started in Kagera, Tanzania. Using the 36-Item Short Form Health Survey (SF-36), 329 HAART recipients were interviewed in May 2007. Questions on sociodemographic characteristics, chronic diseases (besides HIV/AIDS), HAART side effects and adherence to antiretroviral drugs were added. Treatment data, the first and latest available CD4 counts were retrieved from patients' records. Gender and age-adjusted mean scale scores of the sample were compared to those of the general Tanzanian population of the late 1990 s using t test. Logistic regression was used to explore the effect of sex, age, education level, income, chronic diseases, CD4 count, HAART side effects and adherence to antiretroviral drugs on recipients' physical functioning and mental health scale scores. The mean scale scores of HAART recipients were generally lower than those of the general population except for general health perceptions (p = 0.191) and mental health (p = 0.161). HAART recipients with chronic disease comorbidity were more likely to score below the general population's mean score for mental health (p = 0.007). While the effect of chronic disease comorbidity on physical functioning among those who recorded a CD4 count increase was negative (odds ratio [OR] = 13.6, 95% confidence interval [CI] = 3.7, 49.9), there was no effect on those who did not have such an increase. The control of chronic diseases among recipients should be given priority to improve their HRQOL.