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Objective In an effort to reduce mortality from gastric cancer, endoscopic screening was introduced in 2016 as a nationwide screening program in Japan. Recent developments in high-definition endoscopic imaging and diagnostic strategies have enabled the simultaneous detection of other upper gastrointestinal (U-GI) malignancies. Therefore, we conducted a study to evaluate the feasibility of endoscopic screening for U-GI malignancy in a comprehensive health checkup. Methods We retrospectively reviewed the data of 13,120 participants who had received a comprehensive health checkup in a single institution between April 2012 and March 2018. Participants were divided into two groups [gastrointestinal endoscopy (GIE) group (n=9,142) and gastrointestinal X-ray (X-ray) group (n=3,978)] and compared with regards to the screening results, adverse events, and detection rate of U-GI malignancies (gastric cancer or other) using a propensity-score matched analysis. Results The gastric cancer detection rate was significantly higher in the GIE group [34/9,142 (0.48%)] than in the X-ray group [3/3,978 (0.08%)] (p=0.003). Other U-GI malignancies were found only in the GIE group and comprised two hypopharyngeal cancers, five esophageal cancers, two duodenal cancers, and one duodenal gastrointestinal stromal tumor. Adverse events occurred in 6/9,142 (0.07%) participants in the GIE group and 18/3,978 (0.45%) participants in the X-ray group (p<0.0001). A propensity-score matched analysis yielded 1,551 matched pairs, and the detection rate of gastric cancer and other U-GI malignancies remained significantly higher in the GIE group than in the X-ray group. Conclusion This study indicated that not only gastric cancer but also other U-GI malignancies can be detected by endoscopic screening.