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The controversy of distinguishing keratoacanthomas (KAs) from well-differentiated squamous cell carcinomas (WDSCCs) is well established. A number of recent studies have attempted to separate these processes with the use of immunohistochemical stains. In corroboration, we have retrospectively reviewed three groups of patients with tissue biopsies with features of classical KA (n = 7), WDSCC (n = 8), and squamous cell carcinoma with KA-like features (SCC-KA) (n = 9). We compared their clinical and histological differences as well as their immunohistochemical differences using antibodies to proliferating cell nuclear antigen (PCNA), and wild- and mutant-type p53 protein. Classical KA showed a PCNA staining pattern located predominantly around the basal cell layers, in contrast to a relatively diffuse staining pattern seen in WDSCC. SCC-KA showed considerable overlap with these two types of staining patterns. The p53 staining showed basal, patchy, or diffuse patterns. These patterns were present in all three groups. Although both PCNA and p53 expression was more often present in SCC-KA, there were no statistical differences among the groups. In conclusion, the overlapping expression patterns of PCNA and p53 in keratocanthoma-like tumors support the hypothesis that these tumors represent a possible biologic spectrum. Because of the absence of significant statistical differences in the expression of these antigens, PCNA and p53 have not proved to be helpful in differentiating KA from KA-like squamous cell carcinoma.