The pharmacokinetics of benzathine penicillin G (1,200,000 IU given intramuscularly), penicillin V (250 mg given orally twice daily), erythromycin stearate (250 mg given orally twice daily) and roxithromycin (150 mg given orally once daily) were investigated. The drugs were given prophylactically to prevent the recurrence of rheumatic fever to 20 patients attending a rheumatic fever clinic in a study of crossover design. Serum antibiotic concentrations were determined by microbiological assay at intervals of up to 28 days after intramuscular injection and immediately before and 1-2 h after the fifth oral dose. The concentrations of penicillin G in all serum samples obtained on day 28 after parenteral benzathine penicillin G administration were greater than 0.01 mg/dl. Most patients had no detectable penicillin V or erythromycin in blood samples drawn immediately before the fifth dose. The concentration of roxithromycin at 24 h after the dose was greater than 1.2 mg/dl in all patients. Based on the pharmacokinetic profiles, it is suggested that 1,200,000 IU benzathine penicillin G given every 4 weeks is an appropriate regimen for preventing the recurrence of rheumatic fever in Thai adults. Roxithromycin had much better pharmacokinetics than penicillin V and erythromycin stearate, and is probably the best alternative regimen to intramuscular penicillin G.