Background: Interstitial lung disease (ILD) is the major cause of mortality in collagen vascular diseases. However, its pathogenesis still needs to be elucidated. Methods: To evaluate the alteration of certain proteins in bronchoalveolar lavage fluid (BALF) and clarify the causative role in the processes of ILD in systemic sclerosis (SSc), we compared a BALF protein profile between 5 patients with systemic sclerosis with pulmonary fibrosis (SSc-fib+) and 4 patients with systemic sclerosis without pulmonary fibrosis (SSc-fib-) using two-dimensional gel electrophoresis (2-DE), and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). Results: We analyzed spots over the range of 10.1 kDa to 207.4 kDa. SSc-fib+ patients showed increased 3 proteins compared to SSc-fib- including α2-macroglobulin, α1-antitrypsin, and pulmonary surfactant protein A and decreased 2 proteins including α2 heat shock protein (HSP) and glutathione S-transferase (GST) compared to SSc-fib- patients. Conclusions: In conclusion, we identified several interesting proteins that might have roles in ILD of SSc patients. Further studies are warranted to clarify the role of these proteins in the processes of pulmonary fibrosis in SSc.