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Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells that can be challenging to distinguish histologically from Langerhans cell (LC) hyperplasia, seen in a variety of inflammatory dermatoses. Lesional cells in both entities demonstrate positive staining for CD1a and S100. Previous studies have demonstrated positive staining of fascin, CD31, and p53 in cases of LCH, but currently, no studies have compared the staining profiles of these markers between LCH and LC hyperplasia. The authors compared immunohistochemical staining profiles of LCH (n = 15) and various inflammatory dermatoses with LC hyperplasia (n = 15) using fascin, CD31, and p53. Fascin, CD31, and p53 were graded as a percentage of CD1a staining cells in the epidermis and dermis of each specimen. Fascin showed no significant differences in staining between the 2 entities. CD31 was positive in the dermal infiltrate in 40% of cases of LCH and negative in all cases of LC hyperplasia. p53 was positive in the epidermal infiltrate in 50% of cases of LCH, and positive in the dermal infiltrate in 93% of cases of LCH, whereas negative in all cases of LC hyperplasia. Fascin was not a helpful marker in distinguishing LCH from LC hyperplasia. CD31, if positive in the dermal infiltrate, is suggestive of a diagnosis of LCH, but exhibits a relatively low sensitivity for this purpose. p53 proved to be a helpful and accurate diagnostic immunohistochemical stain when distinguishing between LCH and LC hyperplasia.