Abstract Infections during pregnancy can expose the fetus to microbial Ags, leading to inflammation that affects B cell development. Prenatal fetal immune priming may have an important role in infant acquisition of pathogen-specific immunity. We examined plasma proinflammatory biomarkers, the proportions of various B cell subsets, and fetal priming to tetanus vaccination in cord blood from human United States and Kenyan neonates. United States neonates had no identified prenatal infectious exposures, whereas Kenyan neonates examined had congenital CMV or mothers with prenatal HIV or Plasmodium falciparum or no identified infectious exposures. Kenyan neonates had higher levels of IP-10, TNF-α, CRP, sCD14, and BAFF than United States neonates. Among the Kenyan groups, neonates with prenatal infections/infectious exposures had higher levels of cord blood IFN-γ, IL-7, sTNFR1, and sTNFR2 compared with neonates with no infectious exposures. Kenyan neonates had greater proportions of activated memory B cells (MBC) compared with United States neonates. Among the Kenyan groups, HIV-exposed neonates had greater proportions of atypical MBC compared with the other groups. Although HIV-exposed neonates had altered MBC subset distributions, detection of tetanus-specific MBC from cord blood, indicative of fetal priming with tetanus vaccine given to pregnant women, was comparable in HIV-exposed and non–HIV-exposed neonates. These results indicate that the presence of infections during pregnancy induces fetal immune activation with inflammation and increased activated MBC frequencies in neonates. The immunologic significance and long-term health consequences of these differences warrant further investigation.