Background: A significant proportion of upper gastrointestinal cancers (UGICs) remain undetected during esophagogastroduodenoscopy (EGD). We investigated the characteristics and risk factors of UGICs missed during endoscopy.Methods: In this nationwide registry-based study, we analyzed two large Polish datasets (National Health Fund and National Cancer Registry) to identify individuals who underwent EGD and were subsequently diagnosed with UGIC. Cancers diagnosed < 6 months after EGD were defined as "prevalent" and those within ≥ 6- < 36 months as "missed." We compared the characteristics of missed and prevalent cancers, and analyzed the risk factors for missed UGICs in a multivariable regression model.Results: We included 4 105 399 patients (mean age 56.0 years [SD 17.4]; 57.5 % female) who underwent 5 877 674 EGDs in 2012-2018. Within this cohort, 33 241 UGICs were diagnosed, of which 1993 (6.0 %) were missed. Within esophageal neoplasms, adenocarcinomas were more frequently missed than squamous cell cancers (6.1 % vs. 4.2 %), with a relative risk of 1.4 (95 % confidence interval [CI] 1.1-1.8, P = 0.01). Most gastric cancers were adenocarcinomas, of which 5.7 % were classified as missed. Overall, a higher proportion of missed UGICs than prevalent cancers presented at an advanced stage (42.2 % vs. 36.2 %, P < 0.001). Risk factors for missed UGICs included initial EGD performed within primary (vs. secondary) care (odds ratio [OR] 1.3, 95 %CI 1.2-1.5), female sex (OR 1.3, 95 %CI 1.2-1.4), and higher comorbidity (Charlson comorbidity index ≥ 5 vs. 0; OR 6.0, 95 %CI 4.7-7.5).Conclusions: Among UGICs, esophageal adenocarcinomas were missed most frequently. Missed cancers occur more frequently within the primary care sector and are found more often in women and individuals with multiple comorbidities. [ABSTRACT FROM AUTHOR]