The diagnosis of myeloid leukemia cutis can be difficult, particularly in the context of an initial skin biopsy with a malignant hematopoietic neoplasm. We studied the immunohistochemical characteristics of 33 cases of myeloid leukemia cutis diagnosed at Stanford University Medical Center, Stanford, CA, 1996-2007, and compared them with the corresponding bone marrow blast immunophenotype and World Health Organization classification (2008). In the skin, CD43 marked 97% of cases (32/33), myeloperoxidase marked 42% (14/33), CD68 marked 94% (31/33), CD163 marked 25% (7/28), and CD56 marked 47% (14/30). CD34 and CD117 were predominantly negative. In 19 cases in which myeloperoxidase was negative, all marked with CD68 and CD43. The flow cytometric immunophenotype of the leukemic blasts in the bone marrow was discordant with the immunohistochemical profile in the skin in all cases, showing loss or gain of at least 1 antigen. Given the immunophenotypic differences between skin and bone marrow blasts, we provide an updated immunohistochemical approach to the diagnosis of myeloid leukemia cutis.