Background: Kangaroo Mother Care initiated after stabilization reduces mortality in infants with birthweight <2.0 kg, but the majority of deaths occur before stabilization. The safety and efficacy of Kangaroo Mother Care initiated soon after birth is uncertain. Methods: We conducted a randomized controlled trial in five hospitals in Ghana, India, Malawi, Nigeria, and Tanzania. Infants with birth weight between 1.0 and <1.8 kg were randomly assigned to immediate Kangaroo Mother Care (intervention) or to conventional care until stabilization, and Kangaroo Mother Care thereafter (control). The primary outcomes were deaths in the neonatal period (first 28 days of life) and in the first 72 hours of life. The study was stopped early on the recommendation of the DSMB owing to reduced neonatal mortality with the intervention. Results: A total of 3211 infants and their mothers were randomly allocated (1609 intervention, 1602 control group). The median daily duration of skin-to-skin contact in neonatal intensive care units was 16.9 hours (IQR 13.0–19.7) in the intervention and 1.5 hours (IQR 0.3–3.3) in control group. Neonatal death occurred in 191 infants (12.0%) and 249 (15.7%) infants, respectively (RR 0.75; 95% CI 0.64–0.89; p=0.001);death in the first 72 hours of life occurred in 74 infants (4.6%) and 92 infants (5.8%), respectively (RR 0.77, 95% CI 0.58–1.04; p=0.09). Conclusion: In infants with birthweight between 1.0 and <1.8 kg, immediate Kangaroo Mother Care (versus conventional care) resulted in a significant reduction in neonatal mortality, but not in mortality within the first 72 hours.