Background <p>Complex spinal surgery is associated with significant trauma and pain. Herein we tested the hypothesis that increasing the dose of esketamine, as a supplement to patient-controlled analgesia, might improve pain relief after extensive spinal surgery.</p> Methods <p>In this randomized, double-blind, and controlled trial, we enrolled adults who were scheduled to undergo extensive posterior spinal fusion. Participants were randomized in a 1:1:1 ratio to receive patient-controlled sufentanil-dexmedetomidine analgesia supplemented with esketamine at 0.25 (Esk25), 0.5 (Esk50), or 0.75 (Esk75) mg/ml. Our primary endpoint was an integrated index of pain intensity and opioid consumption (ranging from − 200% to + 200%, with higher scores indicating greater pain and/or more opioid consumption) with movement within 72&#xa0;h after surgery.</p> Results <p>A total of 312 patients (median 38 years; 24.4% female) were enrolled and randomized; all were included in the intention-to-treat analysis. The primary endpoint did not differ among three groups (Esk50 vs. Esk25: mean difference − 2 [95% CI -31 to 28]; Esk75 vs. Esk25: mean difference 13 [95% CI -16 to 43]. The proportions reporting nausea/vomiting and nausea were higher in the Esk75 group than in the Esk25 group (nausea/vomiting: 70.2% [73/104] with Esk75 vs. 52.9% [55/104] with Esk25; <i>P</i> = 0.021; nausea: 68.3% [71/104] with Esk75 vs. 49.0% [51/104] with Esk25; <i>P</i> = 0.005).</p> Conclusions <p>For adult patients recovering from extensive posterior spinal fusion, increasing esketamine concentration in patient-controlled analgesia from 0.25 to 0.5 and 0.75&#xa0;mg/ml did not improve pain relief or reduce opioid consumption. Esketamine at a concentration of 0.75&#xa0;mg/ml increased postoperative nausea and vomiting.</p> Trial registration <p>ClinicalTrials.gov, NCT06062550; first submitted on September 25, 2023.</p>