Background - Despite the widespread availability of oral rehydration therapy, diarrheal illness remains a major cause of morbidity and mortality around the world. Previous studies have shown individualized homeopathic therapy to be effective in treating childhood diarrhea, but this approach requires specialized training. Objective: A homeopathic combination medicine, if effective, could be used by health personnel on a widespread basis.Methods - A double-blind randomized controlled trial was conducted in Honduras to evaluate the effectiveness of a homeopathic combination therapy to treat acute diarrhea in children. A total of 292 children with acute diarrhea was recruited; 145 were randomized to the experimental group and 147 to the placebo group. Tablets containing a combined preparation of the five most common single homeopathic remedies used to treat diarrhea or placebo were administered by a parent after each unformed stool. Children were followed up daily for 7 days or until symptoms resolved, whichever occurred first. Time until resolution of symptoms, daily rate of unformed stools, and total number of unformed stools were compared between the two groups.Results - There was no significant difference in the likelihood of resolution of diarrheal symptoms between the treatment and placebo groups (hazard ratio = 1.02, 95% confidence interval: 0.79–1.32), with a median time until resolution of 3 days for both groups. Children in the treatment group had an average of 2.6 unformed stools per day compared to 2.8 among those in the placebo group; this difference was not significant (p = 0.43). The median number of unformed stools was 7 among children in the treatment group and 8 among those in the placebo group (p = 0.41).Discussion - The homeopathic combination therapy tested in this study did not significantly reduce the duration or severity of acute diarrhea in Honduran children. Further study is needed to develop affordable and effective methods of using homeopathy to reduce the global burden of childhood diarrhea.