Background: Dexketoprofen trometamol (DKP.TRIS) is the tromethamine salt of dexketoprofen, the S-enantiomer responsible for the pharmacological activity of ketoprofen. DKP.TRIS has rapid absorption and onset of action in pain relief. Objective: To compare the efficacy and tolerability of DKP.TRIS and diclofenac, a nonsteroidal anti-inflammatory drug widely accepted as reference therapy for symptomatic treatment of osteoarthritis, in patients with chronic pain due to knee osteoarthritis. Design: This was a multicentre, randomised, comparative, double-blind study. Methods: Radiological evidence of osteoarthritis, shown by the presence of Kellgren grade 2 to 4 changes, was required. Patients were evaluated before and after a washout period of 7 to 14 days and after 1 and 2 weeks of treatment with DKP.TRIS 25 mg three times daily orally or diclofenac 50 mg three times daily orally. Primary end-points were reduction of pain measured on a visual analogue scale (VAS, 0 to 100 mm) and disability measured by the Lequesne index of severity for knee osteoarthritis (ISK). Tolerability was evaluated by laboratory parameters and frequency and nature of adverse events. Results: Of 117 patients recruited to the study, 115 were treated (61 with DKP.TRIS, 54 with diclofenac) and 99 (54/45) completed the 2-week treatment period. Patient characteristics were homogenous between groups. Pain measured on the VAS decreased by 43% from 61.7 ± 18.5 mm (mean ± SD) at baseline to 34.7 ± 22.3 mm at the end of treatment with DKP.TRIS compared with a 29% decrease from 62.1 ± 22.7 mm to 40.6 ± 22.2 mm for diclofenac [p = 0.027; 95% confidence interval (CI) for the difference between treatments: 1.7, 27.9]. Median ISK scores improved from 11 (range 9 to 12) to 8 (6 to 10) in the DKP.TRIS group versus 10.75 (9 to 12.5) to 8.5 (6 to 10.5) in the diclofenac group. There were no group differences for secondary end-points. Adverse events were comparable overall between groups. Conclusion: Oral DKP.TRIS 25 mg three times daily is at least as effective as diclofenac 50 mg three times daily for the short term treatment of pain in patients with osteoarthritis of the knee.