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Abstract Background Frunevetmab, a felinized antinerve growth factor monoclonal antibody, effectively decreases osteoarthritis (OA) pain in cats. Objective To evaluate the efficacy of frunevetmab given at monthly intervals in a randomized, placebo‐controlled, parallel‐group, double‐blind superiority study. Animals Two hundred seventy‐five client‐owned cats with naturally‐occurring OA pain and associated mobility impairment and disability. Methods Randomized, placebo‐controlled, parallel‐group, double‐blind, superiority study. Following screening, cats received frunevetmab (nominal dose of 1.0 mg/kg, SC [effective dose range of 1.0‐2.8 mg/kg]) or placebo on days 0, 28, and 56. Outcome measures were owner questionnaires and veterinary physical and orthopedic evaluations at days 28, 56, and 84. Success/failure rates (and numbers needed treat, NNT) and change in scores (and standardized effect size, ES) were analyzed. Results Frunevetmab (182) and placebo (93) treated cats were enrolled and received at least 1 treatment. Significant improvement with frunevetmab over placebo occurred at days 28 and 56 for the client specific outcome measures (CSOM) questionnaire (success rates and total scores [NNT of 9 and ES of 0.3 at day 56]); at days 28 and 56 for owner‐assessed global treatment response; and at days 56 and 84 for veterinarian‐assessed joint pain (ES of 0.18 at day 56). Adverse events did not differ between groups, except skin disorders which collectively occurred significantly more frequently in frunevetmab treated (32/182 cats) vs placebo (8/93 cats). Conclusions and Clinical Importance Frunevetmab has the potential to address a critical gap in the treatment of pain because of osteoarthritis in cats.