The recognition of enterococci highly resistant to streptomycin (S) raises questions concerning the choice of aminoglycoside in treatment of enterococcal endocarditis. Left-sided endocarditis was induced in rabbits with an S-sensitive enterococcus, strain 1 (inhibited by 125 mug per milliliter S), and an S-resistant enterococcus, strain 2 (resistant to 7,500 mug per milliliter S). Treatment was initiated 6 hours, 24 hours, or 3 days after infection with procaine penicillin (P) alone, P plus S, P plus gentamicin (G), or P plus sisomicin (Si). In rabbits infected with strain 1 for 6 hours before treatment, most vegetations were sterile after 3 days therapy with each combination but not with P alone which had mean log10 colony forming units per gram of vegetation (log CFU) of 2.5. With strain 2 the log CFU were lower (1.9 to 2.6) with each combination than with P (4.0). In rabbits infected with strain 1 for 24 hours and then given 9 days of therapy, the log CFU were decreased with each combination (2.0 to 2.3) as compared with P alone (4.9). With strain 2 the log CFU were lower with P plus G or Si (1.5 and 2.5) than with P alone or P plus S (4.5 AND 4.1). In rabbits infected with strain 1 for 3 days and then given 7 days of therapy, the log CFU were 4.1 to 5.5 with each combination and 6.7 with P. With strain 2 the log CFU was 4.0 with P plus G or Si as compared with 6.4 and 6.7 for P or P + S. These studies showed little difference between the 3 antibiotic combinations with the S-sensitive enterococcus or in early (6-hour) endocarditis caused by the S-resistant enterococcus. There was a large advantage of P plus G and P plus Si over P + S in more established (24 hour or 3 day) endocarditis caused by the S-resistant enterococcus.