Various growth factors and cytokines have been suggested to play a central role in initiating and developing fibrosis in systemic sclerosis (SSc). To determine which serum levels of soluble mediators are the most relevant to the degree of skin sclerosis in SSc, serum levels of various soluble mediators were examined by ELISA and correlated with skin thickening that was measured using modified Rodnan total skin thickness scoring (TSS) system. Serum levels of IL-4, IL-12, IL-13, tumor necrosis factor-alpha, connective tissue growth factor (CTGF), vascular endothelial growth factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1beta, soluble IL-6 receptor, and soluble L-selectin were higher in SSc patients than normal controls. Levels of IL-6, IL-10, and CTGF in patients with diffuse cutaneous SSc were higher than patients with limited cutaneous SSc and controls. Serum levels of IL-6 and IL-10 positively correlated with TSS in patients with SSc (r=0.625, P<0.0001 and r=0.663, P<0.0001, respectively). In addition, IL-10 levels significantly correlated with pulmonary fibrosis. Thus, serum levels of IL-6 and IL-10 most strongly reflect the extent of skin thickening in SSc, suggesting that levels of IL-6 and IL-10 are useful serological indicators for skin fibrosis in SSc.