Background: Human papillomavirus(HPV) is associated with some cases of palmoplantar epidermal cysts and suggested to the cyst formation. Recently, a case of HPV-associated epidermal cyst in the genitalia was also reported. Objectives: To evaluate and compare HPV infection sign of the plantar and genital epidermal cysts. Methods: We retrospectively reviewed plantar and genital epidermal cyst cases. We evaluated their histopathologic characteristics and HPV positivity using immunohistochemistry. Results: Sixty cases (20 plantar, 40 genital) were included in this study. Parakeratotic nuclei within keratinous substances were present in 17 of 20 plantar cysts versus 9 of 40 genital cysts (P<0.001). Vacuolar structures in keratinous mass were seen in 7 of 20 plantar versus 6 of 40 genital cysts (P=0.076). Intracytoplasmic eosinophilic bodies in cells of cyst wall were present in 8 of 20 plantar versus 2 of 40 genital cysts (P=0.001). Six of 20 (30%) plantar epidermal cysts had all of the aforementioned histopathologic findings and demonstrated HPV positivity, whereas no genital epidermal cyst did. Conclusion: Histopathologic signs indicative of HPV infection were rarely seen in genital epidermal cysts, compared to plantar epidermal cysts. HPV is unlikely to have a general pathogenic role in the genital epidermal cyst.