Mixed Staphylococcus aureus and Enterobacter endocarditis of the tricuspid valve in a heroin addict failed to respond to large doses of antibiotics to which these organisms were sensitive. However, following tricuspid valvulectomy, the synergistic combination of cefanone and gentamicin sulfate (Garamycin) effectively eradicated the infection. Though the patient tolerated absence of the tricuspid valve for eight weeks, his exercise capacity was limited until a tricuspid valve prosthesis was inserted. The Enterobacter strain isolated from this patient inactivated penicillin and oxacillin in broth culture. Studies of a sonicate from this organism demonstrated considerable β-lactamase activity against penicillin and oxacillin and less against cefanone. Those findings suggest a mechanism by which the presence of Enterobacter perpetuated staphylococcal endocarditis despite prolonged therapy with antibiotics.