Streptococci that colonize the mouth and upper respiratory tract tend to be considered harmless commensals. In 45 cases of acute pneumonia and/or pulmonary abscess and 25 cases of thoracic empyema, the predominant species recovered were anaerobic bacteria and the Streptococcus milleri group, which encompasses the oral species Streptococcus anginosus, Streptococcus constellatus, and Streptococcus intermedius. The isolation of most S. milleri organisms along with oral anaerobes indicated synergy between these groups. Studies in a mouse model of pneumonia demonstrated this synergy; mortality was higher, histopathologic abnormalities were more marked (reflecting acute pneumonia followed by pulmonary abscess or empyema), and viable bacteria were more numerous in the lungs of mice with mixed infections caused by the S. milleri group and anaerobes than in the lungs of those with monomicrobial infection. In vitro studies elucidated a possible mechanism of this synergistic effect: anaerobes may enhance the growth of the S. milleri group and/or inhibit the bactericidal activity of the host. We conclude that the S. milleri group is more important in pulmonary infections than has previously been recognized.