Objective: To assess the efficacy and tolerability of flupirtine in comparison with tramadol for the treatment of moderate to severe subacute low back pain (LBP). Design and methods: In this randomised, double-blind, parallel-group trial, 209 LBP patients, aged 18-65 years, were orally treated with flupirtine 100 mg (n=105) vs. tramadol 50 mg (n=104), both three times daily for 5-7days. Main outcome measures: Patient assessment of pain intensity after 5-7 days (primary); physicians' global assessment of improvement in pain and functional capacity; adverse events. Results: Flupirtine showed an overall pain-relieving efficacy comparable to tramadol. Mean LBP intensity after end of treatment dropped from 6.8 (95% CI: 6.5-7.0) to 2.8 (95% CI: 2.3-3.1) for flupirtine and from 6.9 (95% CI: 6.6-7.1) to 3.0 (95% CI: 2.6-3.4) for tramadol, corresponding to pain relief rates of 57% (95% CI: 51-63%) and 56% (95% CI: 50-62%) respectively (p=0.796), indicating non-inferiority of flupirtine. All other efficacy endpoints supported equivalent efficacy. Adverse events (AEs) occurred significantly less in patients after flupirtine (33%) vs. tramadol (49%) (p=0.02) and both the respective severity grading and the AE-related dropout rates were significantly lower after flupirtine than after tramadol (1% vs. 15%, p<0.001). Conclusion: Flupirtine 100 mg three times daily was associated with a reduction in pain and improvements in functional capacity equivalent to that observed with tramadol 50 mg three times daily, and was better tolerated, when administered to patients with subacute back pain for one week. The limitations of this study were the lack of a placebo control and the short (7-day) duration of the study.