Considering the high prevalence of osteoarthritis (OA) and since until now there has not been any human studies to evaluate the effect of sesame in OA patients, this study was designed to assess the effect of administration of sesame on inflammation and oxidative stress in patients with knee OA. Fifty patients with knee OA were allocated into two groups namely control and sesame group. 25 patients in the control group received 40 g placebo powder per day while 25 patients in the sesame group received 40 g of sesame seed daily during two months of study along with standard medical therapy. Serum total antioxidant capacity, malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) were measured. In the sesame group, a significant decrease in serum MDA and hs-CRP were seen after two months of study (P<0.05). There was no significant difference in post-treatment serum values of MDA, TAC and hs-CRP between two groups (P>0.05). Serum IL-6 decreased significantly in both groups compared with baseline during the two-month study (P<0.05). There was a significant difference in mean serum IL-6 between two groups after treatment (P=0.001). Sesame seed is a natural and safe substance that may have beneficial effects in patients with knee OA, and it may provide new complementary and adjunctive treatment in these patients.