Clusterin and S-protein bind to the membrane attack complex of complement (MAC) rendering it cytolytically inactive. Tissue necrosis as produced by pulsed tunable dye laser therapy (PTDL), and immune complex-related diseases such as lupus erythematosus, are accompanied by local accumulation of MAC. However, the mechanisms responsible for this accumulation might differ, and lead to deposition of MAC in different forms (cytolytically active or inactive). Biopsy specimens of lesional (22) and non-lesional (10) skin from 27 patients with a positive lupus band test (LBT) were studied using monoclonal antibodies against clusterin, S-protein, and MAC by immunofluorescence and immunoperoxidase. Identical studies were performed in normal and angiomatous skin specimens from three normal individuals before and after laser irradiation. MAC was present in 30 of 32 positive LBT skin biopsies. MAC was not only present in lesional (21 of 22) but also in non-lesional skin (nine of 10), although the intensity of staining appeared to be lower in the latter. Clusterin and S-protein co-localized with MAC, respectively, in 20 and 12 specimens, and were not found in the absence of MAC. In addition S-protein deposits were seen only in biopsies positive for clusterin. Deposits of clusterin and S-protein did not correlate with the presence or absence of lesions. After irradiation with PTDL, the immediate complement activation was accompanied by MAC deposits that were granular and clearly located on vascular endothelial cells. Clusterin and S-protein were not present on these cells. In summary, clusterin localizes with MAC along the skin dermal-epidermal junction in patients with a positive LBT, suggesting that it has a similar and possibly more important role than S-protein in regulating immune complex-mediated MAC formation. By contrast, clusterin and S-protein are not involved at the time of MAC formation in cells undergoing necrosis after PTDL therapy.