The large cell acanthoma presents as a slightly scaly tan macule on photodamaged skin. Clinically, it may be difficult to differentiate from a lentigo senilis, pigmented actinic keratosis, or a flat and pigmented seborrheic keratosis. We have studied 19 cases of large cell acanthoma. Large cell acanthomas were identified histologically as having epidermal keratinocytes with nuclei roughly twice the size of adjacent epidermal or adnexal keratinocytes, and as having minimal nuclear pleomorphism. Histologic findings were compared with actinic keratosis and lentigo senilis. Melanocyte density and cellular proliferation were compared using HMB-45 staining of melanocytes and proliferating cell nuclear antigen (PCNA) staining of epidermal keratinocytes. Lentigo senilis and large cell acanthoma both showed increased numbers of melanocytes, as identified by HMB-45 staining. Actinic keratosis shows a statistically increased proliferation rate, as identified by PCNA staining. On the basis of clinical, histologic, and immunohistochemical staining similarities, we believe that large cell acanthoma should be considered as a reaction pattern, possibly related to lentigo senilis.