Carbonic anhydrase II (CAII) is expressed on alveolar epithelium and participates to CO2 elimination, fluid secretion and post-capillary pH regulation. CAII is overexpressed in animal models of lung fibrosis in sites of epithelial injury. Autoantibodies directed against CAII (anti-CAII) have been described in sera from patients affected by systemic sclerosis (SSc), but no study focused on their clinical associations in this disease. The aim of this study was to assess the presence of anti-CAII in sera of SSc patients and to investigate their association with lung involvement. We performed ELISA to detect anti-CAII in 34 SSc patients who underwent pulmonary function tests (PFT) and Doppler echocardiography. We found increased prevalence and significantly elevated serum levels of anti-CAII in SSc patients affected by restrictive lung disease (RLD) compared to SSc patients without lung involvement and healthy controls. These findings suggest both a possible pathogenic role of anti-CAII in the development of lung damage and a potential clinical utility as serological marker of pulmonary involvement in SSc patients.