Weight loss and wasting have long been established as strong predictors of mortality in HIV-infected patients. Today, despite the effectiveness of highly active antiretroviral therapy (HAART), there is evidence that HIV-related wasting is still an important comorbidity in many patients. We conducted a study to determine if wasting is still associated with decreased survival in patients receiving HAART and which parameter (weight, fat-free mass [FFM], body cell mass [BCM], or fat mass [FM]) is most strongly associated with mortality. The study population consisted of 678 HIV-positive participants enrolled in the Nutrition for Healthy Living study. Weight, FFM, BCM, and FM were assessed for all participants at 6-month intervals. At each follow-up visit, percent losses of each parameter were calculated from values at baseline and the previous visit. Cox proportional hazards models were used to estimate and compare the relative risks of death for each parameter, adjusting for potential confounders such as HAART use, body mass index, and CD4 cell counts. In analyses examining the parameters separately and together in the same model, weight loss emerged as the strongest independent predictor of mortality. Weight loss of >or=10% from baseline or the previous visit was significantly associated with a four- to sixfold increase in mortality compared with maintenance or gaining of weight. Even one episode of weight loss of >or=3% from baseline or >or=5% from the previous visit was predictive of mortality. In summary, despite the apparent benefits of HAART use on HIV-related survival, weight loss remains an independent predictor of mortality. In addition, FFM or BCM estimated using bioelectrical impedance analysis does not add further prognostic value over weight loss.