Leukemia cutis (LC) and reactive myeloid infiltrates in the skin may be difficult to distinguish pathologically, sometimes even after an extensive immunohistochemical work-up. This poses a serious clinical dilemma, as the prognosis and treatment of either condition are markedly different. Although most reactive myeloid infiltrates require a simple course of corticosteroids before the symptoms regress, the development of LC may require chemotherapeutic or transplant-variant interventions. Erythroblast transformation specific regulated gene-1 (ERG) is a member of the erythroblast transformation specific family of transcription factors, which are downstream effectors of mitogenic signaling transduction pathways. ERG is a key regulator of cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis and has recently been found to be overexpressed in acute myeloid and lymphoblastic leukemia. In this study, the authors aimed to explore the diagnostic utility of ERG immunohistochemistry in LC by comparing the frequency and expression level of ERG immunostain in 32 skin biopsies, 16 with LC and 16 with reactive leukocytic infiltrates. A significantly higher frequency of ERG positivity was detected in LC (13/16, 81.4%), compared with reactive conditions (0/16). In addition, the expression level of ERG in LC, calculated using H score (mean ± standard error of mean, 188 ± 24), was significantly higher than that in nonneoplastic leukocytic infiltrate (28 ± 8). Our results strongly suggest that ERG expression is potentially an extremely useful marker to distinguish between cases of LC from those of reactive myeloid infiltrates in the skin with a positive predictive value of 100% and negative predictive value of 84.2%.