Lysosome-associated membrane proteins (LAMPs) are integral transmembrane proteins densely expressed on lysosomes which can be shuttled to the plasma membrane during cell activation. The objective of this study was to examine the expression of LAMPs on the cell surface of peripheral blood mononuclear cells (PBMCs) derived from patients with scleroderma. Heparinized blood was obtained from 23 patients with scleroderma and 15 healthy controls and PBMCs were isolated via a Ficoll gradient. Cells were stained with monoclonal antibodies directed against two of the major LAMPs, lamp1 and lamp2, and, after subsequent staining with a fluorescent second antibody, were analyzed by flow cytometry. Two- and three-color immunofluorescence was utilized to define the phenotype of LAMP+ cells. The proportion of PBMCs expressing lamp2 on the cell surfare was significantly elevated in patients with scleroderma (2.21 ± 0.38%) compared to controls (1.14 ± 0.27%; P < 0.05). Multivariate analysis of patient subgroups indicated that the significant factors contributing to higher levels in patients were shorter duration of disease (P < 0.01) and greater functional disability related to disease manifestations (P < 0.01). Patients with anti-Sc170 antibodies had the highest levels of cell surface lamp2 expression (4.19 ± 0.90%; P < 0.0005). The degree of cell surface lamp2 expression correlated with the level of sIL2R in 19 scleroderma patients (r = 0.48; P < 0.05). Serum IL4 and IL6 did not correlate with cell surface LAMPs or sIL2R. Five of 19 patients had detectable serum levels of interleukin-8 (ILS). These patients had significantly higher cell surface lamp2 expression than those with no detectable IL8 (3.76 ± 0.48% vs 1.44 ± 0.39%; P < 0.01). Extended phenotyping revealed that >85% of lamp2+ cells expressed the B-cell antigen CD19. Cell surfare lamp2 expression correlates with clinical and laboratory parameters in scleroderma patients and may reflect immune system activation. Additionally, this is the first report describing an elevation of serum IL8 in an autoimmune or collagen-vascular disease.