Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon cutaneous lymphoma that has been proposed as a distinct clinicopathologic entity, but studies of SPTCL are limited. We studied the clinicopathologic, immunophenotypic, and genetic features of 11 SPTCLs. All cases had a variable admixture of pleomorphic small, medium, or large lymphocytes and histiocytes infiltrating the subcutis in a Iobular panniculitislike pattern. A granulomatous reaction was seen in three cases and erythrophagocytosis in four. Karyorrhexis and fat necrosis were present in all cases. Angioinvasion was seen in seven SPTCLs; four had areas of coagulation necrosis. All cases expressed T-cell-associated antigens (CD3ε, CD45RO, or CD43) and T-cell receptors (TCR); nine expressed αβ TCRs and two expressed γδ TCRs. T- cell receptor-γ, TCRβ, or TCRδ genes were clonally rearranged in 8 of 10 cases studied. Both γδ SPTCLs expressed V(δ)2+ TCRs and were CD4-, CD8- and CD56+. CD56 was negative in seven of nine αβ SPTCLs and inconclusive in the other two. Six of nine αβ SPTCLs were CD8+; the CD4/CD8 phenotypes were indeterminate in the other three. Cytolytic granule-associated proteins were expressed by all SPTCLs (11 of 11 were TIA-1+, 4 of 4 were perforin+). In situ hybridization for Epstein-Barr virus-encoded RNA (EBER-1) was negative in all cases. Most patients responded to systemic chemotherapy or local radiation therapy. Seven patients are alive: four without disease (19- 73 months) and three with disease (32-72 months); four died: three of disease (3-25 months) and one without disease (42 months). We conclude that SPTCLs are clonal, EBV-, cytotoxic T-cell lymphomas derived from αβ T-cells or γδ T-cells. The γδ SPTCLs appear to be preferentially derived from the V(δ)2+ subset. Subcutaneous panniculitis-like T-cell lymphoma may be rapidly fatal or indolent; local therapy may be appropriate for some patients.