ETHNOPHARMACOLOGICAL RELEVANCE: Pistacia atlantica Desf. (Baneh) is a native tree in many areas of Iran such as Zagros mountains and Sistan va Baluchestan Province. It is famous mostly due to its oleo-gum resin and there are many studies on its effects on gastrointestinal disorders and musculoskeletal problems. However, the oil from its fruits is also of use in local communities as a part of their food and for therapeutic purposes such as analgesic effects on joint pains. AIM OF THE STUDY: Osteoarthritis is a widespread form of joint pain in older adults. This double-blinded randomized clinical trial aimed to compare the effects of Baneh fruit oil on knee osteoarthritis with topical diclofenac. MATERIAL AND METHODS: Ninety-two patients with primary knee osteoarthritis were randomly divided into two groups and asked to rub a fingertip of Baneh ointment or diclofenac on their knee 3 times a day for four weeks. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and Visual Analog Scale (VAS) were completed at the beginning, fourth and eighth weeks. The data was analyzed in SPSS software and intention to treat (ITT) analysis was performed. A P-value less than 0.05 was considered statistically significant. RESULTS: After 4 weeks, all parameters improved significantly in both groups but the pain (based on VAS and KOOS), activity, and quality-of-life showed statistically more improvement in the Baneh group (P = 0.001, P <
0.001, and P = 0.009, respectively). Four weeks after stopping the interventions, all parameters in both groups were still significantly better than the baseline (P ≤ 0.05). However, improvement in pain (VAS and KOOS) and activity was stayed better in the Baneh group (P = 0.028, P = 0.001, and P = 018, respectively). Only one case of temporary itching was reported. CONCLUSION: This study revealed that Baneh oil had a positive effect on relieving the symptoms of knee osteoarthritis, however, more clinical trials with longer duration of treatment and larger sample sizes are recommended.