A single-intramuscular-dose immunization regimen with a penicillin G-streptomycin combination was compared with three oral-dose amoxicillin regimens for the capacity to prevent Streptococcus sanguis infections of experimentally induced valvular heart lesions in rabbits. Challenge doses of 10(4), 10(6), and 10(8) CFU of a strain of S. sanguis equally susceptible to penicillin and amoxicillin were used in this study. Measured by recovery of test organisms from endocardial lesions, the lowest concentration of these inocula was infective for 60% of the recipients; the two higher-concentration inocula were infective for all recipients. The penicillin G-streptomycin combination provided complete protection against infection with inocula of all sizes. A single-oral-dose amoxicillin regimen (50 mg/kg of body weight) prevented endocarditis when rabbits were challenged with 10(4) CFU, but protection diminished with increasing inoculum concentrations. Similar results were achieved when five oral doses of amoxicillin (8.5 mg/kg of body weight) added at 8-h intervals were included in the single-oral-dose regimen. In contrast, when rabbits received two oral doses of amoxicillin (50 mg/kg of body weight) with a 10-h interval between doses, prophylaxis was fully effective with even the highest inoculum concentration.