A non-invasive test to facilitate the diagnosis of non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF) is still not available and represents an important goal. Forty-eight patients with stage I NSCLC, 45 with IPF, 30 with other idiopathic interstitial pneumonias (IIPs) including idiopathic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (HP), 35 with diffuse non-malignant disease and 30 healthy donors were enrolled onto the study. Free circulating (fc)DNA and MMP-7 levels were evaluated by Real Time PCR and ELISA, respectively. Median fcDNA levels were similar in NSCLC (127 ng/mL, range 23.6-345 ng/mL) and IPF (106 ng/mL, range 22-224 ng/mL) patients, and significantly lower in IIPs patients, in individuals with other diseases and in healthy donors (p < 0.05). Conversely, median MMP-7 values were significantly higher in IPF patients (9.10 ng/mL, range 3.88-19.72 ng/mL) than in those with NSCLC (6.31 ng/mL, range 3.38-16.36 ng/mL; p < 0.0001), NSIP (6.50 ng/mL, range 1.50-22.47 ng/mL; p = 0.007), other diseases (5.41 ng/mL, range 1.78-15.91, p < 0.0001) or healthy donors (4.35 ng/mL, range 2.45-7.23; p < 0.0001). Serum MMP-7 levels seem to be capable of distinguishing IPF patients from those with any other lung disease. fcDNA levels were similar in NSCLC and IPF patients, confirming its potential role as a biomarker, albeit non-specific, for the differential diagnosis of NSCLC.