The vacuum-assisted closure (VAC) system has become an accepted treatment modality for acute and chronic wounds in adults. The use of negative-pressure dressing has been documented in adults and, to some extent, in children. However, its use in premature infants has not been reported in the literature. The results of using the VAC system were examined in two premature infants with complex wounds. The VAC system was found to be effective in facilitating the closure of large and complex wounds in these patients. Complete epithelialization of the wounds was achieved in both patients without skin grafting. In conclusion, in two premature neonates with extraordinary soft tissue defects, the VAC system was a safe and effective choice to assist in closing these wounds.