Poor growth, micronutrient deficiencies and episodes of diarrhea and respiratory infections occur frequently in HIV-infected children. We investigated whether multi-micronutrient supplementation would improve the growth performance and reduce the number of episodes of diarrhea and/or of respiratory symptoms in HIV-infected children. In a double-blind randomized trial, HIV-infected South African children aged 4-24 months (n = 201) were assigned to receive multi-micronutrient supplements or placebo daily for six months. The children were assessed for respiratory symptoms or diarrhea bi-weekly; weights and heights were measured monthly. In total, 121 children completed the six month follow up study period (60%). A total of 43 children died; 27 of them had received supplements. This difference in mortality was not statistically significant (p = 0.12). Weight-for-height Z-scores improved significantly (p < 0.05) among children given supplements compared with those given placebo (0.40 (0.09-0.71)) versus -0.04 (-0.39-0.31) (mean (95% CI)). Height-for-age Z-scores did not improve in both treatment groups. The number of monthly episodes of diarrhea in the placebo group (0.36 (0.26-0.46)) was higher (p = 0.09) than in the supplement group (0.25 (0.17-0.33)) and the number of monthly episodes of respiratory symptoms was significantly higher (p < 0.05) among children on placebos (1.01 (0.83-1.79)) than those on supplements (0.66 (0.52-0.80)). Multi-micronutrient supplements significantly improved wasting and reduced the number of episodes of diarrhea and respiratory symptoms.