Background: Possible serious bacterial infection (PBSI) is a major cause of neonatal mortality worldwide. We studied risk factors for PSBI in a large rural population in central India where facility deliveries have increased as a result of a government financial assistance program. Methods: We studied 37,379 pregnant women and their singleton live born infants with birth weight >= 1.5 kg from 20 rural primary health centers around Nagpur, India, using data from the 2010-13 population-based Maternal and Newborn Health Registry supported by NICHD's Global Network for Women's and Children's Health Research. Factors associated with PSBI were identified using multivariable Poisson regression. Results: Two thousand one hundred twenty-three infants (6 %) had PSBI. Risk factors for PSBI included nulliparity (RR 1.13, 95 % CI 1.03-1.23), parity >2 (RR 1.30, 95 % CI 1.07-1.57) compared to parity 1-2, first antenatal care visit in the 2nd/3rd trimester (RR 1.46, 95 % CI 1.08-1.98) compared to 1st trimester, administration of antenatal corticosteroids (RR 2.04, 95 % CI 1.60-2.61), low birth weight (RR 3.10, 95 % CI 2.17-4.42), male sex (RR 1.20, 95 % CI 1.10-1.31) and lack of early initiation of breastfeeding (RR 3.87, 95 % CI 2.69-5.58). Conclusion: Infants who are low birth weight, born to mothers who present late to antenatal care or receive antenatal corticosteroids, or born to nulliparous women or those with a parity >2, could be targeted for interventions before and after delivery to improve early recognition of signs and symptoms of PSBI and prompt referral. There also appears to be a need for a renewed focus on promoting early initiation of breastfeeding following delivery in facilities.