PurposeTo evaluate the effect of scheduled intravenous acetaminophen administration versus nonsteroidal anti-inflammatory drugs on postoperative pain and short-term outcomes after esophagectomy.MethodsThe subjects of this study were 150 consecutive patients who underwent esophagectomy for esophageal cancer. Seventy-seven patients received scheduled intravenous acetaminophen and the other 73 received NSAIDs enterally for postoperative pain management. We compared the postoperative pain and short-term outcomes between the groups. Inverse probability of treatment weighting (IPTW) based on propensity scores was used to control for selection bias.ResultsThe visual analog scale (VAS) of postoperative pain was lower in the acetaminophen group than in the NSAIDs group, based on the mean values of chest VAS on postoperative days (PODs) 0, 4, 5, and 6 and the mean values of abdomen VAS on PODs 4, 5, and 6. The incidence of anastomotic leakage and postoperative delirium was lower in the acetaminophen group than in the NSAIDs group (anastomotic leakage, odds ratio (OR) 0.3, p = 0.01; postoperative delirium, OR 0.19, p < 0.01).ConclusionScheduled intravenous acetaminophen administration is effective and feasible for the postoperative pain management of patients undergoing esophagectomy and may be associated with a lower incidence of anastomotic leakage and postoperative delirium.