The exact incidence and importance of side effects associated with methicillin therapy in children is unknown. During the ten-year period from 1964 to 1974 approximately 3,000 Houston children who received methicillin were observed for side effects. The great majority of these patients received the drug for less than ten days; however, side effects were more common in patients receiving long-term therapy. In order to assess these side effects, experiences with 124 children who received methicillin for ten days or longer were reviewed in depth. The average dose of methicillin was 200 mg/kg/day and the average duration was 22 days. In this highly selected group there were no adverse side effects in 54.8% and only eosinophilia in an additional 13%. Leukopenia occurred in 16%, microscopic hematuria in 8%, gross hematuria in 4%, skin rash in 6%, and "drug fever" in 6%. In many instances several of these side effects occurred within a single patient so that the total number of patients with definite side effects was 39 of 124 (31.5%). The true incidence figure of overall side effects is much lower than 31.5%. Corrected incidence rates based on a conservative figure of 3,000 methicillin-treated children are less than 1.5% for all side effects. In some patients the mechanism producing the adverse reactions seemed to be chemical irritation or toxicity and in others hypersensitivity. In nine of the 39 patients follow-up studies were not optimal. In the other 30 patients all side effects were reversible.