Sneddon's syndrome is a rare, but potentially severe, arterioocclusive disorder characterized by generalized livedo racemosa of the skin and various central nervous symptoms due to occlusion of medium-sized arteries of unknown cause. We have recently shown that, in skin, small to medium-sized arteries of the dermis-subcutis boundary are affected in a stage-specific sequence. An initial phase (stage I), characterized by the attachment of lymphohistiocytic cells and detachment of endothelial cells (endothelitis), is followed by an early phase (stage II), which displays partial or complete occlusion of the lumen by a plug of lymphohistiocytic cells and fibrin. In an intermediate phase (stage III), the occluding plug is replaced by proliferating subendothelial cells accompanied by the occurrence of dilated capillaries in the adventitia of the occluded vessel. The late phase (stage IV) shows fibrosis and shrinkage of the affected vessels. We investigated sections of paraffin-embedded specimens of 18 patients by immunohistochemistry using a panel of antibodies to detect endothelial cells, macrophages, T cells, smooth muscle-specific actin, and intermediate filaments (vimentin, desmin). We found that the cells involved in subendothelial proliferation were vimentin and actin positive (smooth-muscle-specific), but desmin negative and thus displayed the phenotype characteristic of smooth muscle cells, which was confirmed by ultrastructural studies. CD3+, UCHL-1+, and HLA-DR+ cells constituted a significant proportion of the inflammatory infiltrate in the early stages. The endothelial cells in the dilated capillaries of the adventitia were strongly HLA-DR positive. In later stages, endothelial cells and leukocytes were scarce. The data confirm the hypothesis that Sneddon's syndrome starts as an inflammatory and possibly immunologically mediated disorder, leading to a migration and proliferation of smooth cells of small arteries, resulting in a partial or complete narrowing of the vessel lumen.