The occurrence of IgE and IgG antibodies to penicillin G and V in children on long-term treatment with penicillin as secondary prophylaxis for rheumatic fever was studied using Phadebas RAST (Pharmacia Diagnostics, Uppsala, Sweden) and ELISA respectively. The duration of the prophylaxis ranged between 1.5 months and 5 years (mean 1.8 years). Of 18 patients who had been given penicillin for more than 1.5 months, two had IgE antibodies and 12 had IgG antibodies to penicillin. Patients with acute rheumatic fever who had not yet received long-term treatment with penicillin had antibodies of the IgG class in two out of 12 cases. The patients gave no history of adverse reactions to the penicillin injections and there were no signs of immune complex-mediated disease. The two children who had IgE antibodies were switched to oral erythromycin instead of the penicillin injections. Penicillin is the drug of choice in the prophylaxis of rheumatic fever and can apparently be safely given as intramuscular injections of depot-penicillin to prevent recurrences of the disease and ensuing cardiac damage.