OBJECTIVE: Studies evaluating predictors of heath-related quality-of-life (HRQOL) in patients infected with HIV have primarily been limited to clinical, sociodemographic, and psychological factors. Little is known about the relationship between HRQOL and behaviors such as medication adherence or complementary and alternative medicine (CAM) use. The purpose of this study was to determine the clinical, sociodemographic, and behavioral predictors of HRQOL. METHODS: A sample of 242 HIV-infected patients was recruited. Data were collected using a self-administered instrument containing the Medical Outcomes Study (MOS)-HIV Health Survey and items relating to CAM use, medication adherence, and sociodemographic characteristics. Clinical information was abstracted from medical records. Independent associations of the Mental (MHS) and Physical Health Summary (PHS) scores with CD4 cell counts, HIV-1 viral loads, CAM use, self-reported medication adherence, antiretroviral use, and sociodemographic characteristics were assessed. Linear regression models were created for each score. Variables independently associated (p < 0.05) with a score were entered into that model. RESULTS: The mean MHS and PHS scores were 46.6 and 42.8, respectively. Education, income, CAM use, and self-reported adherence to HIV medication regimens were independently associated (p < 0.03) with MHS scores. PHS scores were independently associated (p < 0.003) with age, income, HIV-1 viral load, CD4 count, and CAM use. In the multivariate analyses, income and self-reported adherence were found to be significant (p < 0.005) predictors of the MHS scores (Adj. R2 = 0.197); age, income, CD4 counts, and CAM use were found to be significant (p < 0.03) predictors of PHS scores (Adj. R2 = 0.182). CONCLUSIONS: Our research suggests that, along with clinical and sociodemographic characteristics, self-reported behaviors are important predictors of HRQOL among HIV-infected patients.