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Background: Resveratrol is a natural compound found in red wine. It has demonstrated anti-inflammatory properties in preclinical models. We compared the effect of oral resveratrol in a new patented formulation to oral placebo for individuals with painful knee osteoarthritis. Methods and findings: ARTHROL was a double-blind, randomized, placebo-controlled, Phase 3 trial conducted in 3 tertiary care centers in France. We recruited adults who fulfilled the 1986 American College of Rheumatology criteria for knee osteoarthritis and reported a pain intensity score of at least 40 on an 11-point numeric rating scale (NRS) in 10-point increments (0, no pain, to 100, maximal pain). Participants were randomly assigned (1:1) by using a computer-generated randomization list with permuted blocks of variable size (2, 4, or 6) to receive oral resveratrol (40 mg [2 caplets] twice a day for 1 week, then 20 mg [1 caplet] twice a day; resveratrol group) or matched oral placebo (placebo group) for 6 months. The primary outcome was the mean change from baseline in knee pain on a self-administered 11-point pain NRS at 3 months. The trial was registered at ClinicalTrials.gov: (NCT02905799). Between October 20, 2017 and November 8, 2021, we assessed 649 individuals for eligibility, and from November 9, 2017, we recruited 142 (22%) participants (mean age 61.4 years [standard deviation (SD) 9.6] and 101 [71%] women); 71 (50%) were randomly assigned to the resveratrol group and 71 (50%) to the placebo group. At baseline, the mean knee pain score was 56.2/100 (SD 13.5). At 3 months, the mean reduction in knee pain was −15.7 (95% confidence interval (CI), −21.1 to −10.3) in the resveratrol group and −15.2 (95% CI, −20.5 to −9.8) in the placebo group (absolute difference −0.6 [95% CI, −8.0 to 6.9]; p = 0.88). Serious adverse events (not related to the interventions) occurred in 3 (4%) in the resveratrol group and 2 (3%) in the placebo group. Our study has limitations in that it was underpowered and the effect size, estimated to be 0.55, was optimistically estimated. Conclusions: In this study, we observed that compared with placebo, oral resveratrol did not reduce knee pain in people with painful knee osteoarthritis. Trial registration: ClinicalTrials.gov ID: NCT02905799. In a phase 3 trial, Christelle Nguyen and team compared the effect of oral resveratrol in a new patented formulation to oral placebo for individuals with painful knee osteoarthritis. Author summary: Why was this study done?: Resveratrol has demonstrated anti-inflammatory properties in preclinical models and analgesic effects in painful conditions. For individuals with knee osteoarthritis, evidence before the study suggested a reduction in pain and an improvement in function at 3 months after resveratrol supplementation as an add-on therapy with meloxicam as compared with placebo. The optimal formulation of oral resveratrol was not addressed. What did the researchers do and find?: We conducted a double-blind, randomized, placebo-controlled, Phase 3 trial using oral resveratrol in a new patented formulation (Patent No. WO/2010/007252). We recruited adults with knee osteoarthritis who reported a pain intensity score of at least 40 on an 11-point numeric rating scale (NRS) in 10-point increments (0, no pain, to 100, maximal pain). Participants were randomly assigned (1:1) to receive oral resveratrol or matched oral placebo for 6 months. Oral resveratrol did not reduce knee pain at 3 months as compared with matched oral placebo in individuals with painful knee osteoarthritis. What do these findings mean?: These findings do not support the use of resveratrol supplementation for reducing knee pain in adults with painful knee osteoarthritis. The study has limitations in that it was underpowered and the effect size, estimated to be 0.55, was optimistically estimated. [ABSTRACT FROM AUTHOR]