BACKGROUND Streptococcus sanguis currently accounts for one-half of viridans streptococci. Treatment has become complicated due to the increase in resistance to penicillin and cephalosporins. The aim of the study was to assess the efficacy of various antibiotics as monotherapy and in association with gentamicin, in a experimental model of infective endocarditis in rabbits. The effects were compared with a control group and a group given classical penicillin-gentamicin treatment. METHODS Infective endocarditis was induced in 180 rabbits with a clinical isolate of Streptococcus sanguis. Treatment was started 48 h after infection, and lasted 5 days. The animals were divided into nine groups of 20 rabbits: G1, untreated controls; G2, penicillin-gentamicin; G3, clindamycin-gentamicin; G4, imipenem; G5, imipenem-gentamicin; G6, teicoplanin; G7, teicoplanin-gentamicin; G8, vancomycin and G9, vancomycin-gentamicin. Response to therapy was evaluated by mortality curves, as negative blood cultures, concentration of S. sanguis in aortic vegetations and rate of sterilization of vegetations. RESULTS Vegetation weight was significantly lower in treated groups than in controls; lower weights were found in G5, 6, and 9. G9 sterilized 75% of the vegetations. Death occurred in 25% of the control group and in 4.76% of G6 and 7. Blood cultures became negative most rapidly in G9. CONCLUSIONS Combined treatment with vancomycin-gentamicin may be highly efficacious in patients with endocarditis caused by penicillin-resistant Streptococcus sanguis. Other combinations, such as imipenem-gentamicin and teicoplanin-gentamicin, may be also advantageous.