Oral streptococci may cause infective endocarditis in patients with susceptible cardiac disease after dental treatment. Multiple dental visits, each preceded by penicillin prophylaxis, may result in the unwanted development of resistant oral streptococci. This study was undertaken to determine whether resistant oral streptococci would develop after the repeated use of penicillin prophylaxis in healthy adults. Plaque samples were collected from 20 subjects on each Monday for 5 successive weeks. Each subject was administered 2 gm penicillin V followed by 1 gm 6 hours later (standard prophylaxis regimen of the American Heart Association), on three successive Mondays (weeks 2, 3, and 4). The total cultivable oral streptococci and penicillin-resistant oral streptococci were determined for each plaque sample, and representative colonies of resistant streptococci were speciated. During the study, there was a significant increase in the number of subjects who harbored penicillin-resistant oral streptococci. However, with the exception of one subject who had resistant streptococci throughout the study, the number of resistant strains represented only 0.0003% to 0.41% of the total cultivable oral streptococci.