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Clonal seborrheic keratosis (CSK) and pagetoid Bowen disease (squamous cell carcinoma in situ) (PBD) share similar histological features making it sometimes difficult to differentiate the 2. The study group included 29 and 13 cases of CSK and PBD, respectively. Both groups were examined histopathologically (suprabasal mitotic figures, broad rete ridges, crowding of nuclei, nuclear pleomorphism, necrotic keratinocytes, parakeratosis, and dermal inflammation) and immunohistochemically (CK10, Ki-67, and p16). P values for all parameters were calculated using Fisher exact test, 2 tailed. Significant differences were seen regarding mitosis, crowding, nuclear pleomorphism (more common in PBD), and broad rete ridges (more common in CSK). Significant differences were also noted with Ki-67, CK10, and p16 antibodies. Increased Ki-67-positive cells and the presence of >75% positive p16 cells were commonly seen in PBD, whereas CK10-negative cells were a common finding in CSK. A spectrum of staining patterns was observed with CK10 and p16. There is no single reliable criterion to distinguish CSK from PBD. A panel of markers comprising CK10, Ki-67, and p16 seems to be useful in the context of relevant histology.