Yaws is endemic in rural Guyana. An observational study was conducted to determine the efficacy of oral penicillin V therapy in treating skin lesions of yaws in children. In 1999, inhabitants of 7 rural villages near Bartica, Guyana, were screened for skin lesions of yaws. Cases were confirmed by serological testing. A control program was implemented in 2000: children < or =14 years old were screened, and those with active lesions were treated with oral penicillin V for 7-10 days. In 2001, children were rescreened and active cases were treated. Prevalence of yaws skin lesions fell from 5.1% (52 of 1020 children screened in 2000) to 1.6% (8 of 516 in 2001), a 71% drop. Sixteen (94%) of 17 children treated in 2000 and reassessed in 2001 had complete resolution of lesions. A targeted, oral penicillin-based treatment regimen can successfully treat dermatologic yaws in individual children and can decrease the prevalence of skin yaws in a community in which it is endemic. This information may aid in the implementation of additional control efforts.