We studied the clinical significance of S. milleri isolated in our hospital in 68 patients during a 18-month period. In 51 patients (median age: 43 years, no underlying diseases in 29 patients), the isolates were associated with significant infections. They were beta-hemolytic in 32 cases and non-hemolytic in 19. The primary infection sites were the head and neck area (21 cases), the lungs (5 cases of pneumonia), the gastrointestinal tract (12 cases), the urogenital tract (3 cases), the soft tissues (6 cases), and the heart (2 endocarditis). Two septicemias were of unknown origin. Head and neck infections and pneumonia were most often associated with beta-hemolytic strains, and bacteremia, gastrointestinal and urogenital tract infections with alpha-hemolytic strains. S. milleri was found in pure culture in 24 cases. Polymicrobial associated flora (27 cases) was more frequent in the abdominal infections (87%) than in supra-diaphragmatic infections (42%). Severe complications were observed in 12 head and neck infections (57%) (cerebral abscesses 3, lethal mediastinitis 2, osteitis 1, meningitis 1, other suppurative lesions 5). When abscesses were present (27 cases), surgery was required in all cases. Despite the high frequency and severity of local complications, the clinical outcome was usually favorable. However, deaths directly related to S. milleri infections occurred in 2 cases of mediastinitis complicating the course of apparently harmless primary infections. Owing to the possible occurrence of life-threatening complications, S. milleri infections require early identification, treatment and surgery when indicated.