BACKGROUND: Leech therapy was commonly used in traditional medicine for treating localized pain. Clinically significant pain relief after leech therapy for osteoarthritis of the knee has been demonstrated by preliminary data. OBJECTIVE: To evaluate the effectiveness of leech therapy for symptomatic relief of osteoarthritis of the knee. DESIGN: Randomized, controlled trial. SETTING: Outpatient department for integrative medicine of an academic teaching hospital. PATIENTS: 51 patients with osteoarthritis of the knee (leech therapy: 24 patients, mean age [+/-SD], 62.5 +/- 10.2 years; topical diclofenac therapy: 27 patients, mean age [+/-SD], 65.5 +/- 6.7 years). INTERVENTION: A single treatment with 4 to 6 locally applied leeches (leech therapy group) or a 28-day topical diclofenac regimen (control group). MEASUREMENTS: Mean of the pain, function, and stiffness subscores of the Western Ontario and McMaster Universities Osteoarthritis Index and physical sum score of the Medical Outcomes Study 36-Item Short-Form Health Survey with group comparisons at days 3, 7, 28, and 91. RESULTS: The primary end point, pain at day 7, was reduced from a mean (+/-SD) of 53.5 +/- 13.7 to 19.3 +/- 12.2 after leech therapy compared with 51.5 +/- 16.8 to 42.4 +/- 19.7 with topical diclofenac (estimated group difference, -23.9 [95% CI, -32.8 to -15.1]; P < 0.001). Although the difference between group pain scores was no longer significant after day 7, differences for function, stiffness, and total symptoms remained significant in favor of leech therapy until the end of study and for quality of life until day 28. Results were not affected by outcome expectation. CONCLUSIONS: Leech therapy helps relieve symptoms in patients with osteoarthritis of the knee. The potential of leech therapy for treating osteoarthritis and the pharmacologic properties of leech saliva remain to be clarified.