The correct classification of lymphoproliferative disorders provides valuable information regarding subsequent clinical evolution of the disease. The ability of pathologists to distinguish such lesions is generally low, especially when dealing with minimal lymphoid infiltrates. To improve the efficacy of histopathology in the diagnosis of early lesions of mycosis fungoides (MF), we reviewed 24 skin biopsies from 18 patients with patch stage lesions of MF early in the course of their disease and 13 slides of lichenoid, spongiotic, or psoriasiform simulators of MF as a control series. A series of cytoarchitectural features was assessed, and differences in the distribution of histopathologic parameters between the two groups (early MF lesions and MF simulators) were evaluated by the chi-square test and Fisher's exact test. For these parameters, sensitivity and specificity also were calculated. A multivariate log-linear analysis was performed to estimate which of the morphologic parameters yielded independent diagnostic information. We found that the most important feature for the diagnosis of lymphoma was the presence of lymphocytes with extremely convoluted, medium-large (7-9 microm in diameter) nuclei (medium-large cerebriform cells), singly or clustered in the epidermis and in small sheets in the dermis. Additional significant histologic features were epidermotropism as single cells lined up along the basal keratinocytes of the dermal-epidermal junction, absence of significant papillary dermis fibrosis, and absence of significant numbers of dermal blastlike cells. We conclude that the efficacy of single histopathologic features in the diagnosis of early MF is generally poor. Only the presence of medium-large cerebriform cells in the epidermis or in clusters in the dermis proved to be a highly reliable feature. However, the histopathologic diagnosis of early MF lesions and their discrimination from inflammatory simulators can be achieved using the constellation of cytoarchitectural parameters proposed.