OBJECTIVES: The optimal postoperative analgesic strategy after video-assisted thoracoscopic surgery lobectomy remains undetermined. We hypothesized that high-dose preoperative methylprednisolone (MP) would improve analgesia compared to placebo. METHODS: A total of 120 adult patients were randomized equally to 125mg MP or placebo before the start of their elective videoassisted thoracoscopic surgery lobectomy. Group allocation was blinded to patients, investigators and caregivers, and all patients received standardized multimodal, opioid-sparing analgesia. Our primary outcome was area under the curve on a numeric rating scale from 0 to 10, for pain scores on the day of surgery and on postoperative days 1 and 2. Clinical follow-up was 2-3 weeks, and telephone follow-up was 12 weeks after surgery. RESULTS: Ninety-six patients were included in the primary analysis. Methylprednisolone significantly decreased median pain scores on the day of surgery: at rest (numeric rating scale 1.6 vs 2.0, P = 0.019) and after mobilization to a sitting position (numeric rating scale 1.7 vs 2.5, P = 0.004) but not during arm abduction and coughing (P = 0.052 and P = 0.083, respectively). Nausea and fatigue were reduced on the day of surgery (P = 0.04 and 0.03), whereas no outcome was improved on postoperative Days 1 and 2. Methylprednisolone did not increase the risk of complications but increased blood glucose levels on the day of surgery (P < 0.0001). CONCLUSIONS: High-dose preoperative MP significantly reduced pain at rest and after mobilization to a sitting position on the day of surgery, without later analgesic effects. Nausea and fatigue were improved without side effects, except transient higher postoperative blood glucose levels.