Patients with infective endocarditis caused by penicillin-sensitive streptococci (minimal inhibitory concentration less than or equal to 0.1 microgram/ml of penicillin) may be treated successfully with one of the following three regimens: (1) aqueous penicillin G administered intravenously for 4 weeks, (2) aqueous penicillin G administered intravenously for 4 weeks in combination with streptomycin for the first 2 weeks of therapy, or (3) parenterally administered penicillin plus streptomycin for 2 weeks. No substantial difference in the relapse rate exists among the three regimens, and a cure rate of at least 98% may be anticipated with each of the three forms of therapy. The major advantage of the 2-week regimen is that it is more cost-effective than 4 weeks of hospitalization and therapy. The major disadvantage of the 2-week regimen and the 4-week regimen that uses streptomycin is the relatively low risk of streptomycin-associated vestibular toxicity. Patients unable to tolerate penicillin may be treated with vancomycin or a cephalosporin administered parenterally for 4 weeks.