Nitric oxide metabolites (NOx) in serum, and alveolar concentration of NO (CA(NO)), are markers of inflammation and alveolitis, respectively, in systemic sclerosis (SSc). We prospectively evaluated the usefulness of both NOx and CA(NO) to assess lung involvement and skin fibrosis in SSc. Serum NOx, and CA(NO) measured by two different methods, namely the two-compartment (2CM) and the "trumpet" models (TM), were concomitantly assessed in 65 patients with SSc and 17 healthy controls. Whilst serum NOx remained comparable between groups, CA(NO) were significantly higher in SSc patients (n=65, 6.7ppb; 4.8-9.7 and 5.9ppb; 3.9-8.9) as compared with controls (n=17, 3.0ppb; 2.0-3.8 and 1.8ppb; 1.1-2.9, p<0.001, p<0.001) using the 2CM and the TM, respectively). CA(NO) from SSc patients with interstitial lung disease (ILD) (n=26, 8.6ppb; 6.5-10.9 and 8.5ppb; 5.9-10.7) or pulmonary arterial hypertension (n=12, 7.3ppb; 6.5-10.4 and 6.9ppb; 5.4-9.9) were significantly higher as compared with patients without ILD (n=27, 4.9ppb; 3.8-6.5 and 4.7ppb; 2.8-5.7; p<0.001 and p<0.001) using the 2CM and the TM, respectively). CA(NO) assessed either by the 2CM or the trumpet model were directly related to the extent of ILD and inversely related to DLCO. There was no correlation between NOx and ILD, or DLCO. Neither CA(NO) nor NOx was correlated with skin fibrosis and no relationship was found between CA(NO) and NOx. Alveolar concentration of NO, but not serum NOx, closely correlates with the extent of ILD in patients with systemic sclerosis. Neither parameter, however, is related to skin fibrosis.