Invasive group A Streptococcus (GAS) infections can be fatal and can occur in healthy children. A case-control study identified factors associated with pediatric disease. Case-patients were identified when Streptococcus pyogenes was isolated from a normally sterile site, and matched controls (>or=2) were identified by using sequential-digit dialing. All participants were noninstitutionalized surveillance-area residents <18 years of age. Conditional regression identified factors associated with invasive disease: other children living in the home (odds ratio [OR]=16.85, p=0.0002) and new use of nonsteroidal antiinflammatory drugs (OR=10.64, p=0.005) were associated with increased risk. More rooms in the home (OR=0.67, p=0.03) and household member(s) with runny nose (OR=0.09, p=0.002) were associated with decreased risk. Among children, household-level characteristics that influence exposure to GAS most affect development of invasive disease.