Four cases of alpha 1-antitrypsin deficiency associated with panniculitis were reviewed. The following histopathologic characteristics were typically present: (a) large areas of normal panniculus adjacent to severe necrotic panniculitis; (b) acute panniculitis--masses of neutrophils causing necrosis and replacing fat lobules; (c) chronic inflammation and hemorrhage at the periphery of acute panniculitis; (d) focal collection and proliferation of histiocytic cells and lipophages; (e) secondary leukocytoclastic vasculitis in areas of necrosis and lymphocytic vasculitis in areas of severe inflammation, but no evidence of primary vasculitis; (f) phlebothrombosis; and (g) in partial (heterozygous) deficiency, pronounced lipophages and giant-cell replacement of fat cells. Endarteritis obliterans was noted. Direct immunofluorescence study showed C3 deposition in the blood vessels of the panniculus or dermis (or both) in all four cases, and IgM was present in the blood vessels of three. Weak granular deposits of IgM or C3 were seen at the epidermal basement membrane zone in two cases. C3 in endothelial cells of the blood vessels was detected in one case. In general, the immunoreactants in the blood vessels were not dense and probably represent secondary vasculitis. We conclude that all patients with severe panniculitis and ulceration should have alpha 1-antitrypsin levels determined. A deep excisional biopsy specimen with abundant panniculus tissue is required for histopathologic diagnosis.