There are no global screening recommendations for esophageal squamous cell carcinoma (ESCC). Endoscopic screening has been investigated in areas of high incidence in China since the 1970s. This study aimed to evaluate whether an endoscopic screening and intervention program could reduce mortality caused by ESCC. Residents age 40 to 69 years were recruited from communities with high rates of ESCC. Fourteen villages were selected as the intervention communities. Ten villages not geographically adjacent to intervention villages were selected for comparison. Participants in the intervention group were screened once by endoscopy with Lugol's iodine staining, and those with dysplasia or occult cancer were treated. All intervention participants and a sample consisting of one tenth of the control group completed questionnaires. We compared cumulative ESCC incidence and mortality between the two groups. Three thousand three hundred nineteen volunteers (48.62%) from an eligible population of 6,827 were screened in the intervention group. Seven hundred ninety-seven volunteers from an eligible population of 6,200 in the control group were interviewed. Six hundred fifty-two incident and 542 fatal ESCCs were identified during the 10-year follow-up. A reduction in cumulative mortality in the intervention group versus the control group was apparent (3.35% v 5.05%, respectively; P < .001). Furthermore, the intervention group had a significantly lower cumulative incidence of ESCC versus the control group (4.17% v 5.92%, respectively; P < .001). We showed that endoscopic screening and intervention significantly reduced mortality caused by esophageal cancer. Detection and treatment of preneoplastic lesions also led to a reduction in the incidence of this highly fatal cancer.