Perforation, a severe complication of necrotizing enterocolitis (NEC), has a high mortality rate. Recently, we presented a new technique for evaluation of NEC: measuring the CT attenuation coefficient of urine after oral administration of iohexol. We present three cases of neonates with NEC who demonstrated serial increases in urine CT attenuation coefficients, all of whom subsequently deteriorated clinically and radiographically. Surgery in all three cases confirmed severe necrosis and/or perforation. These three cases suggest that the CT attenuation coefficient of urine after oral administration of iohexol may be a more sensitive indicator of NEC severity, progression, and perforation than clinical evaluation and radiography. More investigation is necessary, but eventually, this noninvasive technique may be able to decrease morbidity and mortality by predicting the need for surgical intervention or more aggressive medical management of NEC before perforation occurs.