Background: Chlorzoxazone is a muscle relaxant administered for musculoskeletal pain, and as an analgesic adjunct for post-operative pain. Chlorzoxazone for low back pain is currently not advised due to the lack of placebo-controlled trials. We explored the effect of chlorzoxazone on acute pain after spine surgery. Methods: One hundred and ten patients were randomly assigned to 500 mg oral chlorzoxazone or placebo in this blinded study of patients having spine surgery under general anaesthesia. In the 4 h trial period analgesia consisted of IV patient-controlled analgesia (morphine bolus 2.5 mg). Primary outcome was pain during mobilization (visual analogue scale) 2 h after the intervention. Secondary outcomes were pain at rest, opioid consumption, nausea, vomiting, sedation and dizziness. Results: For pain during mobilization 2 h after intervention, there was no significant difference between groups: 51 (21) vs. 54 (25) mm in the chlorzoxazone and placebo groups, respectively, mean difference 3 mm (95% CI −8 to 10), P = 0.59. For pain during mobilization and at rest (wAUC 1–4 h), there were no significant differences between groups. There was no significant difference in total IV morphine use 0–4 h: median 10 (7–21) vs. 13 (5–19) mg in the chlorzoxazone and placebo groups, respectively, P = 0.82. We found no significant difference in adverse effects. Conclusion: No analgesic effect of single-dose chlorzoxazone was demonstrated in patients with acute pain after spine surgery. Based on these findings, chlorzoxazone cannot be recommended for immediate treatment of acute pain after such procedures.