Cystic fibrosis (CF) is associated with impaired ion transport across epithelial membranes and an increased transepithelial potential difference (PD) that can be measured in airway epithelium. The aim of this study was to investigate the diagnostic value of nasal PD in CF, and to test a modified approach to the measurement of this PD. The reproducibility and diagnostic sensitivity and specificity of nasal PD measurements were tested with the perfusion technique and with a simplified modification of the technique done with a novel, solid-state exploring electrode. With the perfusion method, basal PD values were different in CF patients (mean +/- SEM: -51.6 +/- 0.9 mV, n = 104) than in normal (-15.5 +/- 0.9 mV, n = 58, p < 0.01) subjects. CF patients with acute rhinitis or other nasal pathology had mean PD values that were intermediate between those of the patients and normal and disease-control groups (-28.3 +/- 1.2 mV, n = 40, p < 0.01, different from normal). The diagnostic sensitivity of the perfusion method for CF was 91.3%, and the specificity was 96.4%. PD measurements with the modified technique correlated highly with the results achieved with the perfusion method (r = 0.94, n +/- 158). The measurement of nasal PD effectively distinguishes CF from control subjects. Care must be taken in the interpretation of measurements made on acutely inflamed epithelium. The modified method was simpler than the conventional perfusion technique, and equally effective.