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Context: Atypical regeneration can mimic carcinoma in various epithelia. On endoscopic biopsies, atypical regenerative hyperplasia of the esophagus may show pleomorphism and atypia, simulating esophageal squamous cell carcinoma., Objective: To establish the most useful histologic features to distinguish atypical regenerative hyperplasia from esophageal carcinoma in endoscopic biopsies., Design: To study the frequency and histologic appearance of atypical regenerative hyperplasia, which simulate carcinoma, we reviewed 600 endoscopic biopsies (555 with chronic esophagitis and 45 with carcinomas of the esophagus). We selected those cases in which the differential diagnosis included regenerative atypical hyperplasia versus esophageal carcinoma and cases of atypical regenerative hyperplasia that were mistaken for carcinoma. For comparative purposes, we studied 10 cases of esophageal carcinoma from endoscopic biopsies that were confirmed by esophagectomy., Results: Among the cases with chronic esophagitis, we found 10 biopsies (1.8%) in which atypical regenerative hyperplasia mimicked carcinoma. In 7 cases, there were 4 to 12 years of follow-up, and no patient developed esophageal neoplasm. The remaining 3 patients were submitted to esophagectomy. None of these patients had carcinoma or dysplasia in the esophageal resection (false-positive biopsies). The most useful architectural changes in squamous carcinoma included stromal infiltration by nests, cords, or thin prongs of neoplastic keratinocytes, palisading desmoplasia, and in situ carcinoma in the adjacent epithelium. Malignant keratinocytes showed variable degrees of differentiation with differently shaped and sized cells, squamous epithelial pearls, individual keratinization, and atypical mitosis. In contrast, biopsies with atypical hyperplasia showed detached nests or irregular fragments without stroma and were made up of immature and relatively monotonous medium or small keratinocytes that were intermixed with inflammatory cells. Individual keratinization was rare, and no squamous pearls were seen. Other features of atypical hyperplasia included granulated tissue with atypical endothelial cells, nonatypical mitosis, lymphoid hyperplasia, and the absence of dysplasia or carcinoma in situ. Two biopsies showed stromal pseudoinfiltration as a result of tangential sectioning and were characterized by thick, round prongs composed of keratinocytes that penetrated regions with granulation or the inflamed tissues of esophageal ulcers., Conclusions: Atypical esophageal regenerative hyperplasia may mimic carcinoma in a small percentage of esophageal biopsies. If the histologic changes are not sufficient to establish an accurate diagnosis, medical treatment and subsequent biopsies should be performed, particularly if there are no endoscopic or radiologic data to support the presence of a neoplasm.