Optimal antimicrobial therapy for viridans streptococcal endocarditis remains controversial. Rifampin was bactericidal at <0.2 μg/ml for ten strains of viridans streptococci isolated from patients with endocarditis. Administration of rifampin to one endocarditis patient already receiving penicillin and gentamicin increased the serum bactericidal activity fourfold. Rifampin has been effective in combination therapy for serious staphylococcal and enterococcal infections. The combination of penicillin and rifampin may be an effective, less toxic alternative to penicillin and streptomycin for the treatment of viridans streptococcal endocarditis. © 1983 Southern Medical Association.