Atovaquone-proguanil has been shown to be effective and well tolerated for malaria prophylaxis in residents of countries of endemicity and in nonimmune adult travelers, but data about traveling children are limited. In a randomized, open-label, multicenter prophylaxis trial, 221 nonimmune pediatric travelers (age, 2-17 years) received either atovaquone-proguanil or chloroquine-proguanil. Safety and clinical outcome were evaluated 7, 28, and 60 days after travel. By posttravel day 7, a total of 39 (35%) of 110 atovaquone-proguanil and 41 (37%) of 111 chloroquine-proguanil recipients reported > or =1 adverse event. The data indicate that, over the course of treatment, fewer atovaquone-proguanil recipients had treatment-related adverse events (8% vs. 14%), including gastrointestinal complaints (5% vs. 10%). Two subjects discontinued prophylaxis because of drug-related adverse events; both had received chloroquine-proguanil. Observed compliance with prophylaxis was similar before and during travel, but it was higher for atovaquone-proguanil in the posttravel period. No study participant developed malaria. Atovaquone-proguanil was well tolerated and is an important addition to the limited arsenal of prophylactic agents available to children.