Several factors influence levels of end-tidal carbon monoxide (ETCO). We studied determinants of ETCO corrected for inhaled CO (ETCOc) levels in healthy control subjects and compared ETCOc levels and determinants between healthy control subjects and patients with cystic fibrosis (CF). Thirty healthy control subjects (mean +/- SD age, 23 +/- 6 years) and twenty clinically stable patients with CF, aged 13.5 +/- 3.5 years were included. ETCO was measured with the CO-STAT End-Tidal Breath Analyzer (Natus Medical, Inc., San Carlos, CA), and determinants included lung volume (measured with the multiple-breath helium wash-in method), CO-diffusion capacity, and different expiratory flow rates. In healthy control subjects we found a significant correlation between ETCOc and lung volume (r = 0.64, p < 0.05) and with CO-diffusion capacity uncorrected for VA (r = 0.48, p = 0.02). There was no expiratory flow rate dependency in either group. Patients with CF showed no difference in ETCOc levels compared with control subjects (mean 1.2 +/- 0.4 ppm vs. 1.3 +/- 0.4 ppm, p = 0.32), but patients with CF had lower total lung capacity-helium than healthy control subjects. ETCOc corrected for lung volume was significantly higher in patients with CF compared with control subjects (p < 0.001). We hypothesize that a possible increase in breath CO caused by airway inflammation might be masked by differences in lung volumes between control subjects and patients with CF.