Ligation of the patent ductus arteriosus (PDA) is sometimes complicated by postoperative hypotension requiring vasopressor(s). It is unclear which infants are at risk for this complication. We conducted a retrospective and prospective cohort study to identify risk factors predicting vasopressor use after PDA ligation. Our patients were infants < 37 weeks of gestation who underwent PDA ligation. The primary outcome was the use of vasopressor(s) within 72 hours after PDA ligation, defined as beginning vasopressor(s) or increasing the dose of vasopressor(s). Thirty-two of 100 (32%) study infants required vasopressor(s) after PDA ligation. Infants who had lower birth weights, lower gestational ages, higher ventilator support, or whose mothers had received antenatal steroids had a higher risk of vasopressor use. Infants who required vasopressor(s) were at increased risk of dying before 36 weeks postmenstrual age. Lower birth weight, lower gestational age, and higher respiratory support define a high-risk subgroup of patients in whom the prophylactic administration of vasopressor(s) could be studied.