OBJECTIVE: To examine the effects of laser moxibustion on pain and function in patients with knee osteoarthritis (OA). METHODS: A double-blind randomized clinical trial (4-week treatment, 20-week follow-up) was conducted. A total of 392 symptomatic knee OA patients with moderate to severe clinically significant knee pain were randomly assigned to laser treatment or sham laser control group (1:1). Twelve sessions of laser moxibustion or sham laser treatments on the acupuncture points at the affected knee(s) were performed 3 times a week for 4 weeks. The primary outcome measurement was change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to Week 4. RESULTS: Among the 392 randomized participants, 364 (92.86%) completed the trial. The median WOMAC pain score decreased significantly at Week 4 in the active group than in the sham group (2.1, 95% CI 1.6-2.6, < 0.01). At Week 24, compared to the sham laser, active laser treatment resulted in significant pain reduction and function improvement (3.0, 95% CI 2.5-3.6, < 0.01, and 14.8, 95% CI 11.9-17.6, < 0.01, respectively). The physical component of the quality of life significantly improved in the active group vs the sham controls at Week 4 (3.2, 95% CI 1.3-5.0, = 0.001) up to Week 24 (5.1, 95% CI 3.3-7.0, < 0.001). No serious adverse effects were reported. CONCLUSION: Laser moxibustion resulted in statistically and clinically significant pain reduction and function improvement following a 4-week treatment in patients with knee OA.