51 patients with symptomatic knee osteoarthritis were randomized to receive 12 weeks of specialized pro-resolving mediators (SPM) supplementation via soft gels (n=23) or a placebo with olive oil (n=28). The primary outcome of interest was the change in Visual Analog Scale (VAS) pain score from baseline at 12 weeks follow-up. Secondary outcomes included joint function according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), constant/intermittent/total pain scores on the OMERACT-OARSI score, and health-related quality of life on the EuroQoL-5 questionnaire. Follow-up was continued up to 24 weeks (12 weeks after completion of treatment). VAS pain scores at 8 and 12 weeks were significantly lower in the SPM group; the improvement in intermittent pain scores was significantly greater in the SPM group, and total pain score improvement trended in favor of the SPM group. More patients in the SPM group showed significant improvement in EQ-VAS scores in the usual activities dimension compared to the placebo group. The results of this study suggest SPM supplementation could provide significant improvement in pain and quality of life for patients with knee osteoarthritis, however, it has little residual effect after cessation of treatment.