The primary sites of infection and principal reservoirs for transmission of group A streptococci are the nasopharyngeal mucosa and the impetigo lesion. However, pharyngitis and impetigo are rarely observed prior to invasive disease, and, thus, the origin of invasive strains is largely unknown. As part of an active surveillance program, group A streptococci were obtained from normally sterile tissue sites of Connecticut residents during a 6-month period. Organisms were analyzed for genetic markers that distinguish between strains that use the nasopharynx versus an impetiginous lesion as their primary site for infection. The nasopharyngeal marker was observed for most sterile-site isolates, suggesting that the upper respiratory tract is the principal reservoir from which organisms causing invasive disease are disseminated. Genotypic analyses of sterile-site isolates support the view that additional factors, aside from a recent emergence of a few virulent clones, are important contributors to invasive group A streptococcal disease.