-BACKGROUND: Despite the use of intraoperative opioid analgesia, postoperative pain is often reported by patients -ndergoing craniotomies. Opioids also cause undesirable side effects in neurosurgical patients. Hence, the role of nonopioid analgesia has been explored for craniotomies in recent years.-METHODS: This systematic review evaluated evidence from randomized controlled trials (RCTs) comparing opioid and nonopioid analgesia during craniotomies regarding postoperative pain, recovery, and adverse events.-RESULTS: Of the 10,459 records obtained by searching MEDLINE, Embase, and Web of Science databases, 6 RCTs were included. No difference was observed in pain scores between opioid and nonopioid analgesia at 1 and 24 hours after surgery: mean difference (MD), 1.11 units; 95% con-fidence interval [CI],-0.16 to 2.38, P = 0.09 and MD,-0.06 units; 95% CI,-1.14 to 1.01, P = 0.91, respectively. The time for first postoperative analgesic requirement was shorter with opioids but was not statis-tically significant (MD,-84.77 minutes; 95% CI,-254.65 to 85.11; P = 0.33). Postoperative nausea and vomiting (relative risk = 1.60; 95% CI, 0.96-2.66; P = 0.07) was similar but shivering (relative risk = 2.01; 95% CI, 1.09-3.71; P = 0.03) was greater in the opioid group than non-opioid group.-CONCLUSIONS: There were no important differences in clinical outcomes between the groups in our review. The GRADE certainty of evidence was rated low for most out-comes. Available evidence does not suggest superiority of intraoperative nonopioid over opioid analgesia for post-operative pain in patients undergoing craniotomy. More studies are needed to firmly establish the role of nonopioid intraoperative analgesics as an alternative to opioids in this population.