Therapeutic effects of racemic mefloquine were assessed in Schistosoma mansoni-infected mice, and evaluated by recording worm burden, the status of egg maturation and viability, and intestinal mast cell recruitment. Age-matched mice were divided into four groups, of which two were infected. At 8 weeks postinfection, one group of infected and one group of uninfected mice were treated with a single dose of mefloquine (150 mg/kg). Ten days after treatment, all animals were killed. Mefloquine at 150 mg/kg had no effect on worm burden, but significantly reduced the number of eggs in the first three developmental egg stages. Analysis of intestinal mast cell numbers showed that mefloquine induced mastocytosis both in infected and control animals. In conclusion, mefloquine significantly reduces egg production in S. mansoni-infected mice, suggesting a therapeutic potency in schistosomiasis therapy. Mefloquine also exerts a significant proinflammatory effect on the intestine. Through its effect on egg production, mefloquine may be a cause of silent schistosomiasis in travelers using mefloquine for malaria chemoprophylaxis. Further study of the anti-schistosomal activity of mefloquine is warranted, as its activity against other helminths.