Background. Keratoacanthorna (KA) is easily confused with squamous cell carcinoma (SCC) on a clinical or a histopathologic basis. However, KA undergoes spontaneous regression, whereas SCC does not. Objective: Our objective was to study the histopathologic features associated with clinical regression in KA-like lesions to support the therapeutic option. Methods: Forty-three biopsies of KA-like lesions were taken at patient admission. One month later, surgical excision was performed in 18 growing lesions. Regressing lesions were left untreated. Classic histopathologic features and diagnosis were blindly recorded in both biopsies and surgical specimens. Results: On a clinical and a histologic basis, 32 lesions were assessed as KA and 11 as SCC. Features that indicated malignancy were observed in both groups, but the probability of SCC was 31 times higher in tumors with five or more of such features. Several of the histologically atypical lesions were found to regress. Conclusion: SCCs and KAs have more pathologic similarities than differences, especially in the proliferative phase. The combination of the most useful features did not allow the nosologic diagnosis in difficult cases but helped. Differential diagnosis was easier to determine after the 1-month follow up. Complete surgical excision should be indicated in nonregressing and growing lesions.124163173