Fifty-three of 177 infants with necrotizing enterocolitis (NEC) developed portal vein air (PVA). These infants were evaluated for prenatal, perinatal, therapeutic, clinical, laboratory, radiographic, and operative factors as they related to infants with and without PVA. A significantly higher incidence of PVA was seen in infants with NEC who weighed less than 2400 g (P less than 0.025). The use of Vitamin E (P less than 0.01), aminophylline, and high-density premature formula (P less than 0.001) was associated with an increased incidence of PVA. NEC totalis was seen in 55% of the infants with NEC and PVA (P less than 0.001). The presence of PVA was associated with a 58% mortality rate (P less than 0.05). Infants with NEC and PVA operated on prior to 1983 had a 71% mortality. Since 1983, seven of nine infants with NEC and PVA survived early operation using PVA as an indication for surgical intervention. In infants at risk for this highly lethal form of NEC, the avoidance of enteral feedings or altered dietary intake, cautious placement of arterial catheters and the judicious application of pharmacologic agents (eg, Vitamin E, aminophylline) is of importance in regard to prevention. These observations suggest that PVA is a sign of advanced disease and that these high-risk patients should be considered candidates for early surgical intervention.