In rats with catheter-induced sterile aortic valve vegetations we studied the efficacy of single-dose amoxicillin and single-dose erythromycin prophylaxis for the prevention of bacterial endocarditis after extractions of periodontally diseased teeth. Endocarditis after extractions occurred in 89% of control animals and was due to group G streptococci, to Staphylococcus aureus, or to both organisms. A single-dose of amoxicillin or erythromycin successfully prevented endocarditis due to these bacterial species. The analysis of the bacteremia (by culturing blood drawn 1 min after extraction on penicillinase-containing blood agar plates) indicated that amoxicillin did not influence the incidence or the magnitude of circulating group G streptococci and S. aureus, while erythromycin apparently suppressed them. However, when care was taken to eliminate blood erythromycin by a lysis-centrifugation process, the incidence and magnitude of bacteremia after erythromycin prophylaxis was similar to that in control rats. We conclude that single doses of amoxicillin and erythromycin successfully prevent experimental endocarditis after dental extractions. Since this prophylaxis was operative by mechanisms other than the prevention of the circulation of bacteria before seeding the valvular vegetations, it suggests that recommendations for prevention of bacterial endocarditis should not be aimed only at providing adequate antibiotic blood levels to suppress the bacteremia produced by the invasive procedure.