OBJECTIVE--To evaluate the efficacy and safety of ceftriaxone sodium in the treatment of streptococcal endocarditis. DESIGN--An open, multicenter, noncomparative study with a follow-up of patients for 4 months to 5 years. SETTING--Internal medicine wards and outpatient clinics of hospitals of various sizes in three European countries. PATIENTS--Fifty-nine patients with defined criteria for streptococcal endocarditis. INTERVENTION--Ceftriaxone sodium administered at a once-daily dose of 2 g for 4 weeks. MAIN OUTCOME MEASURES--Clinical outcome and microbiological cure rate. RESULTS--Among the 59 patients, 55 completed the treatment and were followed up for 4 months to 5 years. No patients showed evidence of relapse. Treatment was completely uneventful in 42 patients (71%). A cardiac valve was replaced in four patients (7%) receiving antimicrobial therapy and in six patients (10%) who had completed antimicrobial therapy. One of the 10 valves taken for culture at surgery was positive, but only for microorganisms that were different from the microorganism isolated before the treatment. The treatment had to be interrupted in four patients because of drug allergy. Other side effects were mild except for two cases of reversible neutropenia. The treatment was easy to administer: 27 patients (46%) had no permanent intravenous catheter at any time, seven patients (12%) had such a catheter for less than 4 days. Twenty-three patients (39%) were discharged from the hospital less than 2 weeks after admission. --Ceftriaxone sodium administered at a once-daily dose of 2 g appears to be an effective and safe treatment of streptococcal endocarditis. In hospitals, this agent may be more convenient to administer than penicillin G with or without aminoglycosides. Some patients may even be treated as outpatients.