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Abstract Background Vitamin E has a positive effect in the management of osteoarthritis in humans, and in a previous study of dogs. It has been suggested to decrease C‐reactive protein concentrations and liver enzyme activities in humans and animals. Objective To assess the effect of vitamin E supplementation on lameness, pain, pain medication requirement, clinical pathology variables, and quality of life in large‐breed dogs with naturally occurring osteoarthritis. Animals Fifty‐seven client‐owned dogs with naturally occurring osteoarthritis. Methods Dogs received either vitamin E or placebo for 90 days in a randomized, placebo‐controlled, double‐blinded, prospective clinical trial. Clinical lameness scores, pain medication requirements, and owner questionnaires were used to assess response to treatment every 30 days. Blood samples were collected at enrollment and at the end of the study period. Results Vitamin E administration did not improve pain, lameness, or quality of life as assessed by owners and veterinarians. Vitamin E supplementation did not decrease the requirement for rescue pain relief. No changes in clinical pathology variables were observed after 90 days of vitamin E supplementation. Body weight was negatively associated with the lameness scores and requirement for rescue pain relief. Conclusion Vitamin E supplementation did not have any observable positive effects in dogs with naturally occurring osteoarthritis.