A 2-week course of ceftriaxone (2 g) plus netilmicin (4 mg/kg), administered as one short daily iv infusion, was evaluated for the treatment of streptococcal endocarditis in an open multicenter study. Of the 52 patients, 31 were infected with viridans streptococci, 18 with Streptococcus bovis, two with Gemella morbillorum, and one with group C Streptococcus; 48 patients were assessable. Infection was cured in 42 cases, 35 treated medically and seven treated both medically and surgically. Five patients died without evidence of active infection, and one relapsed. The bacteriologic failure was due to a strain of G. morbillorum against which no synergy of ceftriaxone and netilmicin was evident in vitro. The serum creatinine level increased during treatment in four cases, all involving patients > 65 years old who had renal risk factors; in two of these cases, values did not return to baseline during follow-up. Of 40 patients assessed for auditory function, only one developed decreased perception of borderline significance. Other adverse reactions were mild. This regimen was efficacious, safe, and cost-effective for the treatment of streptococcal endocarditis. However, it must be used with caution for patients with preexisting renal impairment or concomitant exposure to other potentially nephrotoxic agents.