Although the incidence of most AIDS-defining opportunistic infections, including HIV wasting syndrome, has dramatically decreased since the introduction of highly active antiretroviral therapy (HAART), previous studies have shown that weight loss and wasting are still common in HIV-infected persons. We examined the 6-month risk and determinants of > or =5% weight loss during the period when the use of combination antiretroviral therapy and HAART was commonplace among 713 participants enrolled in the Nutrition for Healthy Living cohort in Boston, Massachusetts between 1995 and 2003. There was a significant 50% increase in the 6-month risk of > or =5% weight loss in the later HAART years (1998-2003) compared with the early HAART years (1995-1997) among most of the participants who reported they were not trying to lose weight (P = 0.002). In addition to calendar time, several other variables were significantly independently associated with risk of > or =5% weight loss, including use of injection drugs; living below the federal poverty level; higher body mass index (BMI; > or =25 kg/m(2)); lower CD4 cell count; higher HIV viral load; and presence of diarrhea, nausea, or fever. The characteristics of weight loss in the later HAART years did not differ from the early HAART years with respect to initial body composition (eg, weight, BMI, triceps skinfold thickness) or changes in body composition during the periods of weight loss. In summary, we have found that the risk of > or =5% unintentional weight loss over 6-month intervals is on the rise in our cohort of HIV-infected participants, despite better control of HIV infection in recent years. Although we still do not know the exact cause of this increase, the fact that it exists indicates the need for clinicians who take care of HIV-infected patients to continue to pay attention to weight loss among particular segments of their patient population. This is particularly important because recent studies have shown that even a 5% weight loss in 6 months markedly increases the risk of death.