This study investigated the biological pathways underlying infant mortality and maternal factors influencing immune development in HIV-exposed uninfected (HEU) infants. Maternal inflammation (measured by C-reactive protein, CRP) and cytomegalovirus (CMV) viremia were independently associated with infant deaths. Mortality risk doubled with each log10 increase in maternal CRP and increased 1.6-fold with each log10 increase in maternal CMV viral load. Sex-specific differences were observed: mortality in girls was more strongly associated with maternal CRP, while in boys, it was more strongly linked to CMV. HEU infants at one month of age exhibited a distinct immune milieu characterized by elevated soluble CD14 and altered CD8 T-cell compartments, with greater alterations in boys than girls. These findings highlight the sex-differentiated impact of the pregnancy immune environment on infant mortality and immune development in HEU infants.