We investigated three patients suffering from angiocentric lymphoma with granulomatous panniculitis in the skin. All three patients presented with multiple purple subcutaneous nodules. Immunohistologically, the lymphoma cells in all three patients expressed CD2 (T-11), CD56 (neural cell adhesion molecule), and Mik-beta 1 (interleukin-2 beta receptor). CD3s (CD3, Leu-4)-positive lymphoma cells were found in two patients. A pore-forming protein (perforin) was detected in the lymphoma cells of all three patients. Perforin-possessing lymphoid cells were focally scattered in 2 of 15 patients with CD56-negative cutaneous lymphomas who served as controls. By the Southern blot method, one patient showed a rearranged T-cell receptor (TcR)beta gene in the biopsied specimen, and the other two patients had germ-line configurations of TcRs and immunoglobulin heavy chain genes. One patient had serum anti-human T-cell lymphotropic virus (HTLV)-I antibody, but showed no integration of its proviral DNA. Ultrastructurally, membrane-bound azurophilic granules were detected in the atypical lymphoid cells of all three patients. Angiocentric lymphoma with panniculitis in three patients showed the characteristics of natural killer and large granular T-cells. The histological features might be due to the characteristics of the neoplastic cells with azurophilic granules and perforin.