A post-hoc analysis of the previous iKMC trial (N Engl J Med 2021;384:2028-2038) which was conducted in five level 2 Newborn Intensive Care Units in Ghana, India, Malawi, Nigeria, and Tanzania, in neonates with birth weight 1 to <1.8 kg. The intervention was immediate KMC continued until discharge, compared to conventional KMC initiated after meeting stability criteria. 1609 newborns were enrolled in the intervention group and 1602 newborns in the control group. Sepsis related mortality was 37% less in intervention group than the control group; RR 0.63 (CI 0.47–0.85). The intervention group had fewer cases of Gram-negative isolates. Immediate KMC is an effective intervention to prevent neonatal sepsis and sepsis related mortality.