We aimed to investigate the clinical significance of serum levels of secretory leukocyte protease inhibitor (SLPI), which is widely expressed in lung tissues and serves as a useful marker reflecting the activity of various lung diseases, in patients with systemic sclerosis (SSc). Serum SLPI levels were measured by a specific enzyme-linked immunosorbent assay (ELISA) in 58 SSc patients and 16 healthy controls. Serum SLPI levels in diffuse cutaneous SSc and in limited cutaneous SSc with interstitial lung disease (ILD) were significantly higher than those in healthy controls (43.1 ± 18.4 vs. 30.9 ± 3.76 ng/ml, p < 0.05 and 39.8 ± 10.3 vs. 30.9 ± 3.76 ng/ml, p < 0.01, respectively). The incidences of decreased percent diffusing capacity for carbon monoxide (%DLco) and decreased percent vital capacity (%VC) were significantly greater in SSc patients with elevated SLPI levels than in those with normal levels (73 vs. 31%, p < 0.01 and 24 vs. 4%, p < 0.05, respectively). Furthermore, serum SLPI levels were inversely correlated with %DLco (r = -0.40, p < 0.01), while they were positively correlated with surfactant protein D (r = 0.28, p < 0.05). Longitudinal study revealed the association of serum SLPI levels with the disease activity of SSc-ILD. SLPI serves as a useful serum marker for evaluating SSc-ILD.