We previously demonstrated that oxidative stress subsequent to gastroesophageal reflux is an important driving force of esophageal adenocarcinoma (EAC) formation in the esophagogastroduodenal anastomosis (EGDA) rat model. This study investigated the possible tumor inhibitory effects of 2 antioxidants, alpha-tocopherol (389 and 778 ppm), N-acetylcysteine (NAC, 500 and 1,000 ppm), and their combination (389 and 500 ppm, respectively), as well as an antacid therapeutic agent, omeprazole (1,400 ppm). The rats were fed experimental diets 2 weeks after EGDA. All the animals were sacrificed 40 weeks after EGDA and the esophagi were harvested for histopathological examination. alpha-Tocopherol dose-dependently decreased the incidence of EAC (p = 0.03), with 778 ppm alpha-tocopherol reducing the incidence of EAC to 59% (16/27) in comparison with 84% (26/31) in the control group (p = 0.04). Supplementation of alpha-tocopherol also increased the serum concentration of alpha-tocopherol. NAC at 500 and 1,000 ppm did not significantly decrease EAC incidence; however, the combination of alpha-tocopherol 389 ppm and NAC 500 ppm significantly reduced the incidence of EAC to 55% (15/27) (p = 0.02). alpha-Tocopherol alone or in combination with NAC significantly reduced the number of infiltrating cells positively stained for 4-hydroxynonenal. Omeprazole showed only a slight nonsignificant inhibitory effect at the dose given. Our results suggest that supplementation with alpha-tocopherol inhibits the development of EAC in the rat EGDA model and similar inhibitory effect can be achieved when a lower dose of alpha-tocopherol is used in combination with NAC.