Because bacteriostatic concentrations of vancomycin are effective in prophylaxis against endocarditis due to Streptococcus sanguis in rats, the efficacy of three other bacteriostatic antibiotics was investigated against three different streptococcal species that cause subacute endocarditis in humans: Streptococcus intermedius. S. sanguis, and Streptococcus mitior. Rats were challenged by intravenous injection of 2 x 10(5) colony-forming units of streptococci 24 hr after intracardiac insertion of a transaortic catheter and 30 min after intravenous injection of various doses of clindamycin, erythromycin, and doxycycline. Significant protection was achieved with all three antibiotics, but only clindamycin was fully effective against all three species at doses that simulated serum levels achievable in humans after oral administration. Endocarditis was prevented by antibiotic concentrations in serum far below minimal bactericidal concentrations for these streptococci. Furthermore, serum at the time of bacterial challenge was not bactericidal. Therefore, single doses of nonbactericidal antibiotics prevented endocarditis in rats by mechanisms other than bacterial killing.