Macrophages may play a role in the pathogenesis of systemic sclerosis (SSc), and CD163-positive M2 macrophages are potentially important source for fibrosis-inducing cytokines. However, no link between M2 macrophages and SSc has been established. The aim is to evaluate the possibility that serum levels of soluble CD163 (sCD163) can be a useful marker for SSc, reflecting M2 activation of macrophages in this disease. Serum sCD163 levels of 43 patients with SSc, 10 patients with scleroderma spectrum disorder (SSD), and 12 healthy controls were measured with specific enzyme-linked immunosorbent assays. SSc patients had significantly higher serum sCD163 levels than healthy controls. The sCD163 levels in SSD patients were higher than healthy controls and lower than SSc patients. Significantly higher right ventricular systolic pressure and lower % DLco levels, and shorter duration of disease were seen in SSc patients with elevated serum sCD163 levels than those with normal levels. These results suggest that sCD163 levels may be increased in proportion to the progression of this disease, indicating the involvement of CD163 in the pathogenesis of SSc. Furthermore, serum sCD163 levels may be a marker of pulmonary hypertension at the early stage in patients with SSc.