During January and August, 1990, 23 cases of early onset Group B Streptococcus (GBS) disease occurred in a Kansas City, MO, hospital with an attack rate of 14/1000 live births, compared with an annual rate of 1.2 cases/1000 live births for 1988 through 1989. Case infants were compared with controls matched by birth weight, race, maternal age and day of delivery and to a second group of infants of mothers colonized with GBS to identify risk factors and consider intervention strategies during the outbreak. The presence of multiple serotypes among the invasive strains suggested that the outbreak was not caused by a common source. Case mothers were more likely than control mothers to have chorioamnionitis, intrapartum fever or rupture of membranes > 12 hours, and premature case infants were more likely to have a history of rupture of membranes before onset of labor. Multiparous mothers of case infants were more likely to have a history of spontaneous abortion (odds ratio, 6.7; 95% confidence interval, 1.0 to 45.9). No single factor could explain the increase in GBS disease. If intrapartum antibiotic prophylaxis had been used for selected GBS carriers based on presence of either rupture of membranes > 12 hours, intrapartum maternal fever or preterm labor, 7.4% of all deliveries would have received antibiotics and 73% of cases could potentially have been prevented. We conclude that identification of colonized mothers with perinatal risk factors and use of intrapartum antibiotics could be expected to prevent substantial disease during an outbreak of early onset GBS disease.