The authors examined the impact of potent antiretroviral therapy (ART) on the diagnosis of wasting syndrome in the Multicenter AIDS Cohort Study. Study time was divided into the periods 1988-1990, 1991-1993, 1994-1995, and 1996-1999 to correspond to different treatment eras. The proportion of acquired immunodeficiency syndrome diagnoses in which wasting was present increased from 5% in 1988-1990 to 7.1% in 1991-1993, 7.7% in 1994-1995, and 18.9% in 1996-1999. The incidence of wasting per 1,000 person-years increased from 7.5 in 1988-1990 to 14.4 in 1991-1993 and 22.1 in 1994-1995; it decreased to 13.4 in 1996-1999. Fewer patients with wasting had low hemoglobin and hematocrit levels and reported oral thrush in 1996-1999 than in any other period. Analysis of change in body mass index (weight (kg)/height (m)(2)) after wasting showed a faster return to prewasting levels in 1994-1995 and 1996-1999 than in earlier periods. Case-control analysis showed that wasting prior to 1996 was weakly associated with fatigue (p = 0.10), low hemoglobin (p = 0.11), and CD4-positive T-lymphocyte count (p = 0.04). During 1996-1999, wasting was weakly associated with diarrhea (p = 0.05) and potent ART (p = 0.097). Predictors of wasting have changed with potent ART. Further research is needed to determine whether lipodystrophy may be misdiagnosed as wasting syndrome.