Abstract Background The decrement in utility attributable to side effects from combination antiretroviral therapy (CART) is unknown and likely to influence clinical decisions regarding CART initiation and cost-effectiveness. Objective To quantify the decrement in utility attributable to side effects from CART. Methods We estimated SF-6D utilities (quality-of-life weights on a scale from 0.29 worst possible health to 1.00 perfect health) from SF-12 scores among patients with HIV in the Veterans Aging Cohort Study by using a published and validated conversion algorithm. We then compared utilities among patients who: 1) did not have bothersome symptoms while taking CART; 2) had bothersome symptoms that they thought might be due to CART; and 3) had bothersome symptoms that they were confident were due to CART; we controlled for other characteristics known to influence quality of life and stratified analyses by CD4 count. Results Among 1864 patients with available data, symptoms perceived to be attributable to CART were associated with a mean (95% confidence interval) decrement in utility of 0.06 (0.05, 0.08) points in univariate analyses and 0.08 (0.06, 0.10) in multivariable analyses, clinically significant differences that are comparable to utility decrements reported for partial impotence or mild angina. Other significant predictors of changes in SF-6D utilities were hazardous alcohol consumption, recent drug use, cigarette smoking, homelessness, and African American race ( R2 = 0.12). Stratifying by CD4 count, symptoms attributable to CART side effects decreased utility by 0.03 to 0.08 points. Conclusions Symptoms perceived to be related to CART are associated with a substantial decrement in utility.