Effective reduction of HIV replication by protease inhibitor (PI) treatment was expected to reverse some of the weight loss associated with HIV infection. Body weight changes in undernourished HIV-infected patients starting PI treatment were compared to its virologic and immunologic effects. This was designed as a retrospective study using prospectively collected weight data; the setting was the HIV outpatient department of a university hospital. Among 223 consecutive HIV-positive patients starting treatment with PI February 1996 to September 1997, 63 undernourished patients were evaluable. The main outcome measures were weight trend, calculated by linear regression of a patient’s weight versus time, and its change from a 4–14-wk baseline period to the first 14 wk, and 28 wk, after treatment. In our results, weight trend remained unchanged (baseline, + 0.4 ± 4.0 kg/100 d; 14 wk, + 0.7 ± 4.1 kg/100 d, and 28 wk, + 1.0 ± 3.4 kg/100 d, n.s.). Reduction of viremia and increase in CD4 cell count were unrelated to weight trends. Treatment with PI did not result in an improved weight trend. Altered body composition with PI treatment, as observed in other studies, does not seem to result in body weight changes. Drug side effects may have counteracted any positive effects. The metabolic and nutritional impact of effective antiviral treatment merits further study.