Background The effectiveness of endoscopic screening for upper gastrointestinal (UGI) tract cancers in high-risk areas of China has been well-established. However, the practicality of extending this screening to a wider geographical area remains uncertain. To bridge this gap, we have conducted a hospital-based opportunistic endoscopic screening (OpENS) program for UGI cancers since 2018. Our objectives were to elucidate the implementation process of the OpENS program and assess its effectiveness. Methods 875 hospitals from 710 districts/counties have participated in the OpENS program during 2019-2023. The endoscopic specialists and pathologists participating in the program were mandated to take annual training programs to acquire the fundamentals of screening techniques. Eligible patients who underwent endoscopic examinations were screened for UGI cancers. Patients diagnosed with high-grade intraepithelial neoplasia (HGIN), carcinoma in situ (CIS) and tumors in esophagus or/and stomach were defined as positive cases. Patients with HGIN and CIS were defined as early cases. All hospitals were required to submit screening data via the program's platform, with both the quality of the submitted data and the hospitals' performance being subject to a comprehensive evaluation. The age-standardized incidence rates (ASIRs) for the districts/counties where the participating hospitals were situated were derived from the cancer registry data for the year 2020. Districts/ counties with ASIRs for UGI cancers over 22.0/105 were classified as high-risk areas. The positive detection rate (PDR) and early diagnosis rate (EDR) were calculated. Findings After data cleaning, we included 808 hospitals from 616 districts/counties, with a collective participation of 7,066,892 individuals during 2019-2023. The overall PDR and EDR across all sites were 2.35% and 19.77%. The PDRs and EDRs were 1.02% and 23.18% in esophagus, and were 1.37% and 17.80% in stomach. The PDR was higher among males compared to females (3.59% vs 1.20%), and was increasing with age. The EDR was higher among females compared to males (20.66% vs 19.45%), peaking in the age group of 60-64 years. The PDRs and EDRs were higher in high-risk areas of UGI cancers (p < 0.05). After adjusting for age, sex, province, year of screening, regional UGI cancer incidence level and hospital tier, the hospitals that consecutively participated in the program for five years demonstrated higher PDRs and EDRs when compared to other hospitals (p < 0.05). Among the consecutively participated hospitals, tertiary-level hospitals demonstrated positive associations with the PDRs for both the esophagus and stomach when compared to secondary-level hospitals (p < 0.001). However, the tertiary-level hospitals showed a negative association with the EDR for the esophagus (OR = 0.91, 95% CI: 0.86-0.96, p = 0.001), but exhibited a positive association with the EDR for the stomach (OR = 1.11, 95% CI: 1.05-1.17, p < 0.001). Interpretation The OpENS program has rapidly expanded across the country. The program has demonstrated high PDRs and EDRs, with hospitals that performed well exhibiting significantly better screening outcomes. Among these well-performed hospitals, secondary-level hospitals can achieve comparable results to tertiary-level hospitals in screening for esophageal lesions, albeit not for stomach lesions. Considering the current hospital capacities in China, the training-guided opportunistic UGI endoscopy screening exhibits significant feasibility and effectiveness across areas with varying level of UGI risks. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).