In evaluating histologically malignant infiltrates in the skin, it is often challenging to distinguish granulocytic sarcoma (GS) from selected cases of peripheral T-cell lymphoma (PTCL). These lesions have clinical features in common, in addition to shared histologic attributes. These include similarity in dermal distribution and growth pattern, nuclear characteristics, propensity to recruit other inflammatory cell types, and production of matrical sclerosis. In order to determine if immunohistology could contribute to differential diagnosis in this setting, we analyzed 15 cases of mucocutaneous GS, and compared them with 11 cases of well-documented PTCL. Antibodies in the CD15, CD20, CD34, CD43, CD45, CD45RO, and CD68 groups were used, as well as anti-myeloperoxidase (anti-MPX), anti-lysozyme (anti-LYSO), Mac387, and MB2. Anti-LYSO and anti-MPX were sensitive and specific markers of GS, labeling 93% and 80% of GS cases, respectively, and no cases of PTCL. Anti-CD15 and MB2 were also specific for GS, but each labeled only 60% of GS cases. CD34, CD68, and Mac 387 were specific but insensitive markers of GS. CD43 and CD45 were not particularly useful discriminants, with each being seen in 93% of GS cases, but also 64% and 100% of cases of PTCL, respectively. CD45RO was specific for PTCL; it was present in 82% of PTCL cases and no GS cases. Thus, conjoint reactivity for CD43, CD45, MPX, and LYSO characterizes GS, and differs from the pattern of PTCL, which is characterized by reactivity for CD45 and CD45RO, occasional reactivity for CD43, and lack of other specified markers.