The clinical and microbiologic features of Cardiobacterium hominis endocarditis in four patients seen at the Mayo Clinic from 1971 through 1976 are described. All four were men ranging in age from 39 to 60 years. The precipitating factor in three was a dental procedure, and the illness was a prolonged, chronic one, with symptoms having been present 10 to 18 months before diagnosis. The other patient had a late prosthetic valve endocarditis and had had symptoms for only 3 months. Three patients were cured; the fourth died after 32 days of adequate therapy and what was considered a bacteriologic cure. Because of the pronounced fastidiousness of these bacteria, in vitro susceptibility tests could be done in only two of the four; the minimum inhibitory concentration for penicillin G was 0.07 microgram/ml in both. The therapeutic regimens were penicillin G plus streptomycin in the first case, predominantly penicillin G alone in the second, penicillin G for 2 weeks in the third, and ampicillin for 4 weeks in the fourth (prosthetic valve case) in addition to valve replacement. Clinical and laboratory experiences in the total reported cases lead us to believe that 3 weeks of therapy with penicillin G or ampicillin alone is adequate therapy for C. hominis endocarditis of natural valves.