Streptococcus pneumoniae is not a well-recognized cause of soft-tissue infections. In less than 4 years, 12 cases of pneumococcal soft-tissue infection were identified through discussions with infections disease subspecialists in the Philadelphia area. Principal sites of involvement included skin and fascia, tongue, epiglottis, thyroid, brain, and breast. Pneumococcal bacteremia was documented in six cases (50%); in three of these, pneumococci were also cultured from the involved soft tissues. In the cases in which bacteremia was not demonstrated, pneumococci were isolated from the infected sites. Six patients had connective tissue diseases, of which five were diagnosed as systemic lupus erythematosus. Four of these patients were receiving corticosteroids when their infections developed. Two additional patients were HIV-seropositive intravenous drug users. S. pneumoniae may be a more important cause of soft-tissue infections than previously appreciated, especially in patients with connective tissue diseases.