BACKGROUND: Zinc supplementation in young children has been associated with reductions in the incidence and severity of diarrheal diseases, acute respiratory infections, and malaria. OBJECTIVE: The objective was to evaluate the potential role of zinc as an adjunct in the treatment of acute, uncomplicated falciparum malaria; a multicenter, double-blind, randomized placebo-controlled clinical trial was undertaken. DESIGN: Children (n = 1087) aged 6 mo to 5 y were enrolled at sites in Ecuador, Ghana, Tanzania, Uganda, and Zambia. Children with fever and >or=2000 asexual forms of Plasmodium falciparum/ micro L in a thick blood smear received chloroquine and were randomly assigned to receive zinc (20 mg/d for infants, 40 mg/d for older children) or placebo for 4 d. RESULTS: There was no effect of zinc on the median time to reduction of fever (zinc group: 24.2 h; placebo group: 24.0 h; P = 0.37), a >or=75% reduction in parasitemia from baseline in the first 72 h in 73.4% of the zinc group and in 77.6% of the placebo group (P = 0.11), and no significant change in hemoglobin concentration during the 3-d period of hospitalization and the 4 wk of follow-up. Mean plasma zinc concentrations were low in all children at baseline (zinc group: 8.54 +/- 3.93 micro mol/L; placebo group: 8.34 +/- 3.25 micro mol/L), but children who received zinc supplementation had higher plasma zinc concentrations at 72 h than did those who received placebo (10.95 +/- 3.63 compared with 10.16 +/- 3.25 micro mol/L, P < 0.001). CONCLUSION: Zinc does not appear to provide a beneficial effect in the treatment of acute, uncomplicated falciparum malaria in preschool children.