The risk of the future development of primary esophageal cancer after endoscopic esophageal mucosal resection of esophageal cancer is not known; hence, there are no established guidelines for follow-up surveillance programs. Simultaneous occurrence of multiple cancers associated with esophageal cancer is common among heavy drinkers who have the inactive form of aldehyde dehydrogenase-2 (ALDH2) as a risk factor. Thirty-four Japanese male alcoholics with intraepithelial or mucosal squamous cell carcinoma in the esophagus were treated by endoscopic esophageal mucosal resection, followed by endoscopy and esophageal iodine staining, to find the additional development of primary esophageal cancer. Primary esophageal squamous cell carcinoma was detected in nine patients (26.5%) at 3-21 months after the first cancer diagnosis. Cancer occurred more frequently in patients with inactive ALDH2 than it did in those with active ALDH2 [42.1% (8 of 19) versus 6.7% (1 of 15), P = 0.047], and it occurred more frequently in those with multiple esophageal cancers than it did in those without them [60.0% (6 of 10) versus 12.5% (3 of 24), P = 0.009]. Kaplan-Meier estimates of the proportions of patients with additional primary esophageal cancers showed that patients with inactive ALDH2 (P = 0.024) or multiple esophageal cancers (P = 0.007) had a significantly increased likelihood of the development of additional cancer. Close follow-up examinations using endoscopy and iodine staining are needed for such high-risk patients.