The effect of penicillin on the number of oral Streptococcus mutans, Streptococcus sanguis and lactobacilli in hamsters and in man was investigated. This is of interest as S. mutans and lactobacilli are involved in the carious process while S. sanguis is not. Hamsters infected with both S. mutans and S. sanguis or only S. sanguis received penicillin in their drinking water for 14 d. The treatment reduced the proportion of S. mutans and S. sanguis in dental plaque to undetectable levels. After the penicillin treatment the population of S. mutans and S. sanguis gradually increased. In man, the effect of oral penicillin therapy was examined in 21 adults with more than 2 X 10(5) S. mutans per ml saliva. The penicillin treatment had almost no effect on the numbers of S. sanguis and lactobacilli, but a pronounced decrease in the number of S. mutans was observed. The duration of this effect, however, was short. Consequently, such treatment alone is of limited value for the control of the oral infection of these microorganisms.