Unlike other viridans streptococci, members of the "Streptococcus milleri group" are often associated with abscess formation, but are only rare causes of infective endocarditis. Although it has been shown that almost all S. intermedius isolates and most S. constellatus isolates, but only 19% of S. anginosus isolates, were associated with abscess formation, no report has addressed the relative importance of the 3 species of the "S. milleri group" in infective endocarditis. During a 5-year period (April 1997 through March 2002), 6 cases of "S. milleri" endocarditis (out of 377 cases of infective endocarditis), that fulfil the Duke's criteria for the diagnosis of infective endocarditis, were encountered. All 6 "S. milleri" isolates were identified as S. anginosus by 16S ribosomal RNA (rRNA) gene sequencing. Three patients had underlying chronic rheumatic heart disease and 1 was an IV drug abuser. Five had monomicrobial bacteremia, and 1 had polymicrobial (S. anginosus, S. mitis, Granulicatella adiacens, and Slackia exigua) bacteremia. Two patients died. None of the 6 isolates were identified by the Vitek system (GPI) or the API system (20 STREP) at >95% confidence. All 6 isolates were sensitive to penicillin G (MIC 0.008-0.064 microg/mL), cefalothin, erythromycin, clindamycin, and vancomycin. Accurate identification to the species level, by 16S rRNA gene sequencing, in cases of bacteremia caused by members of the "S. milleri group", would have direct implication on the underlying disease process, hence guiding diagnosis and treatment. Infective endocarditis should be actively looked for in cases of monomicrobial S. anginosus bacteremia, especially if the organism is recovered in multiple blood cultures.