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Risk factors for early onset disease (EOD) caused by Group B streptococci (GBS) that are the foundation of prevention guidelines were identified in studies conducted in a few hospital centers. We investigated cases of EOD identified through laboratory-based active surveillance during 1991 and 1992 in a multistate population of 17 million. Ninety-nine cases were compared with 253 controls matched for hospital, date of birth and birth weight. Prematurity (<37 weeks of gestation) was present in 28% of cases; 53% of case mothers had rupture of membranes >12 hours; and 48% reported intrapartum fever. The incidence of EOD in each surveillance area was higher among blacks. By multivariate analysis, case mothers were more likely than controls to have rupture of membranes before labor onset (adjusted odds ratio 8.7, P < 0.001), intrapartum fever (adjusted odds ratio 11.9, P < 0.001), and history of urinary infection during pregnancy (adjusted odds ratio 4.3, P < 0.05). Young maternal age was also associated with risk of disease. Three-fourths of case mothers had intrapartum fever, <37 weeks of gestation and/or prolonged rupture of membranes, indicators previously used to select high risk women for intrapartum chemoprophylaxis. Our findings extend data from single hospitals and suggest prenatal screening and selective intrapartum chemoprophylaxis of high-risk mothers could potentially prevent the majority of EOD in the United States.