By a double blind cross over design, prophylaxis of streptococcal skin disease by long acting benzathine penicillin was studied in 78 children from 18 families with a history of experience with this problem. The prevalence and the incidence of skin lesions were significantly reduced during a 6 wk follow up period after penicillin therapy. The duration of protection was variable, but the majority of children were protected for at least 4 wk. Less protection was observed in younger children, due du to either age or dose related factors. Skin lesions were more prevalent in younger children, irrespective of the type of injection given. Group A streptococci were more frequently recovered from normal skin than from skin lesions after penicillin administration. No indirect protection from disease that might have been conferred by other family members who received prophylaxis was observed in children who, because of allergy, received no injections. Ninety five percent of streptococcal isolates were M typable, and differences were noted in the distribution of specific serotypes from various body sites.