OBJECTIVE: To examine the burden of side effects in patients receiving anti-retroviral therapy METHODS: We reviewed literature on relationships between side-effects, adherence and quality of life in HIV infected patients and developed an exploratory survey to assess impact of side-effects of anti-retroviral therapy on patient's lives. We pilot tested the survey in a small sample of HIV infected patients. The revised survey was web-enabled and made accessible to patients through HIV/AIDS web sites. The survey contained questions on presence of side effects, their impact on work, social life, family, lifestyle and self-perception as well as strategies used by patients to manage their side effects. An exploratory factor analysis using maximum likelihood estimation and oblique rotation was performed on questions about impact to determine the latent dimensional structure of "burden" of side effects as perceived by HIV patients. RESULTS: Four hundred one respondents (mean age=43 years, 88% male) completed the survey. More than 80% of respondents were on regimens with 3 or more anti-retroviral medications. Fatigue (reported by 64% of respondents), diarrhea (62%), sleep problems (49%), lipodystrophy(48%) and sexual dysfunction (44%) were the most commonly reported side-effects. More than 80% of patients indicated that side effects impacted their life at least moderately when reporting impact on a 5-point Likert scale. To make the side-effects less bothersome 26% reported skipping or spacing out doses, 50% reported requesting their physician to change their medication and 20% reported discontinuing their medication altogether. Exploratory factor analysis suggested a unidimensional factor structure accounting for 84% of the variance in underlying latent trait. CONCLUSIONS: Side effects of anti-retroviral therapy can impose significant humanistic burden on HIV patients that should be more thoroughly assessed in clinical trials.