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Introduction: Patients undergoing craniotomy for tumor resection often experience moderate to severe postoperative pain. Intravenous acetaminophen has been proposed as an analgesic adjunct to potentially decrease opioid requirements and incidence of nausea in these patients allowing for prompt postoperative neurological evaluations. At this time, however, there is no evidence to show that acetaminophen reduces patient pain or opioid consumption after craniotomy. Methods: A retrospective analysis of 81 patients undergoing craniotomy was done to evaluate the effect of IV acetaminophen (APAP) administration on reported pain scores, opioid usage, time in the post-anesthesia care unit (PACU), and incidence of nausea within the first 24 hours. Results: No significant differences in patient reported pain scores, opioid consumption within the first 24 hours, anti-emetic use, or time in PACU were found in patients who received intravenous acetaminophen compared to those who received opioids alone. Discussion: Our investigation represents the first evidence looking for an effect of acetaminophen on post-craniotomy pain and nausea. There are randomized and blinded trials currently in progress that will add to our knowledge on this topic. Acetaminophen is a relatively safe intervention. However, until those randomized trials are completed and reported, we cannot uniformly recommend the intraoperative administration of intravenous acetaminophen to patients undergoing craniotomy.