Objective To investigate the effect of vitamin E on the level of oxidative stress and the clinical efficacy in patients with osteoarthritis of the knees. Methods The patients with osteoarthritis of the knees in our hospital were prospectively collected from January to December 2016, and divided into an observation group and a control group with 40 cases in each group. The patients of both groups received routine treatment. And the patients in the observation group received additional oral administration of vitamin E. The whole course was 6 months. The oxidative stress reaction and clinical efficacy were compared between the two groups. Results There was no significant difference in the level of glutathione peroxidase or superoxide dismutase between the two groups before treatment (P > 0.05). After 6-month treatment, the levels of glutathione peroxidase [(122.73 ± 25.65) vs. (145.92 ± 26.74) μmol/L, P < 0.05] and superoxide dismutase [(104.82 ± 18.94) vs. (122.68 ± 19.84) u/ml, P < 0.05] decreased in the observation group compared with the control group. There was no significant difference in pain score, joint stiffness score, daily activity score or total score of Western Ontario MacMaster University Osteoarthritis index (WOMAC) between the two groups before treatment (P > 0.05). After 6-month treatment, when compared with the control group, the patients in the observation group got decreased pain score, joint stiffness score, daily activity score and total score of WOMAC (P < 0.05). There was no statistical difference in Lysholm knee motor function score between the two groups before treatment (P > 0.05). After treatment for 6 months, the score of Lysholm knee motor function in the observation group was higher than that in the control group [(75.21 ± 10.85) vs. (66.48 ± 10.44), P < 0.05]. Conclusions Vitamin E can reduce the level of oxidative stress in the patients with osteoarthritis of the knees and improve the joint function of the patients.