Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen-related superfamily of proteins, is expressed on the surface of macrophages, T cells, and endothelial cells and directly cleaves prothrombin to thrombin. The aim of this study is to determine the serum FGL2 level and its association with clinical parameters in patients with systemic sclerosis (SSc). Serum FGL2 level was examined by enzyme-linked immunosorbent assay in 61 patients with SSc, 24 patients with systemic lupus erythematosus, and 24 healthy individuals. In a retrospective longitudinal study, sera from 13 patients with SSc were analyzed. The serum FGL2 level was increased in patients with SSc compared with healthy individuals (P < 0.001) and patients with systemic lupus erythematosus (P < 0.01). Among patients with SSc, there were no differences in serum FGL2 level between limited cutaneous SSc and diffuse cutaneous SSc. In the longitudinal study, the FGL2 level was generally unchanged at follow-up. The results show that the serum FGL2 level was increased in patients with SSc but not in patients with systemic lupus erythematosus or healthy individuals. Therefore, FGL2 possibly contribute to the development of SSc.