• Two toddlers who attended the same day-care center were hospitalized hours apart with sepsis and meningitis due to a multiply resistant Streptococcus pneumoniae. We determined the prevalence of multiply resistant S pneumoniae respiratory carriage and disease in infants, toddlers, and staff in the day-care center and in household contacts. The nasopharynges of 82 (96%) of 85 day-care center children, 26 (90%) of 29 day-care center staff, and 28 (90%) of 31 family members were cultured. Streptococcus pneumoniae grew from 29 (35%) of the 82 cultured day-care center children. Ten (34%) of the S pneumoniae isolates were resistant to sulfamethoxazole-trimethoprim, oxacillin, and tetracycline and were relatively resistant to penicillin (minimum inhibitory concentration, 0.5 mg/L). All were serotype 14 and had the same antibiotic resistance pattern. Treatment of 97% of the day-care center children and staff with rifampin (10 mg/kg twice daily for 2 days) resulted in 70% reduction in positive nasopharyngeal cultures for S pneumoniae. No additional disease due to multiply resistant S pneumoniae was identified in the day-care center during a 9-month followup period. This report documents that an outbreak of multiply resistant invasive S pneumoniae occurred in a day-care center setting; that nasopharyngeal colonization of exposed children was common; and that rifampin treatment of 2 days only partially eradicated the organism from colonized individuals.