Background and AimEsophageal squamous papilloma (ESP) is a benign growth in the esophagus with unknown malignant potential. The mechanism underlying ESP formation is unknown, but human papillomavirus (HPV) infection has been proposed as a potential etiology. We sought to investigate the clinical characteristic of ESP in our population, review the current literature, and highlight the role of HPV.MethodsThis is a retrospective case–control study conducted at two referral centers. We selected the ESP population by free‐text search in the pathology department database and selected controls randomly from the general endoscopy population. Immunostains were used to evaluate ESP tissue for HPV.ResultsBetween January 2016 and December 2021, we identified 66 patients with ESP, with a prevalence of 0.72%. ESP patients were younger, with a median age of 52 years (P = 0.021), and more likely African American (34.4 vs 7.5%, P < 0.001) compared to controls. On endoscopy images, the growth was predominantly solitary (92.5%) in the middle of the esophagus (39.4%), with sizes ranging from 0.2 to 2.3 cm. A total of 62 patients had available tissue for HPV immune staining, and none tested positive for HPV. Eighteen patients had a follow‐up endoscopy with an average of 504.5 days follow‐up period. One patient developed esophageal squamous cell carcinoma during follow‐up.ConclusionsWe observed a higher prevalence of ESP compared to previous studies. The formation of ESP is multifactorial and partially explained by HPV infection in selected populations. The malignant potential of ESP is low but not negligible.