The definitive diagnosis of mycosis fungoides (MF)-type cutaneous T-cell lymphoma (CTCL) is difficult because a cumulative set of information is typically required: clinical features, histopathology, and special diagnostic tests (typically immunophenotyping and T-cell receptor gamma [TCRgamma] gene rearrangement). Fresh tissue is not always available for the special tests. We report a simple and readily available procedure evaluating the staining pattern on formalin-fixed, paraffin-embedded skin that can help with the diagnosis of patch/plaque stage MF. We reviewed 92 cases of MF or probable MF that had clinical information, immunophenotyping and TCRgamma gene rearrangement studies and that had been evaluated in our multidisciplinary lymphoma conference. We used antibodies to the isoforms of CD45, CD45RO for mature T cells and CD45RB for subsets of T cells. When atypical CD45RB-positive/CD45RO-negative cells were seen in nonspongiotic epidermis, the individuals had a high cumulative clinical and histologic score for MF. In contrast, 15 cases of known contact dermatitis showed a reactive pattern of both CD45RB- and CD45RO-positive cells in spongiotic epidermis. We compared the epidermal CD45RB-positive/CD45RO-negative staining pattern with CD7 deficiency by immunophenotyping and TCRgamma gene rearrangement, two commonly used methods in the diagnosis of MF. The epidermal CD45RB-positive/CD45RO-negative staining pattern is comparable and may be better in equivocal cases of possible MF. Therefore immunostaining for CD45RB and CD45RO on paraffin sections is a simple, reliable, and convenient modality in the diagnosis of MF.