Nasal potential difference (NPD) measurements have been proposed to assess defective ion transport in cystic fibrosis (CF). Implementing it routinely is, however, difficult. Therefore, a modified method based on nasal instillation in supine position at reduced flow rate was tested to evaluate its ability to discriminate CF from non-CF subjects. Classical and modified methods were compared in nine healthy subjects and there were no statistical differences. Following the new method, 97 tests were performed on 74 subjects divided in three cohorts: 21 CF patients and two control groups consisting of 19 patients with other pulmonary diseases and 34 healthy subjects. Twenty five children were enrolled in this study. Maximal NPD in CF patients (-44.9 +/- 2.5 mV) was significantly different from that obtained in control groups (-18.1 +/- 1.6 and -17.2 +/- 1.1 mV). Depolarization after amiloride also discriminated CF patients (25.9 +/- 1.4 mV) from control groups (10.5 +/- 0.9 and 8.1 +/- 0.7 mV). Marked repolarization following isoprenaline plus amiloride in low chloride solution was seen in control groups (-15.7 +/- 1.1 and -15.3 +/- 1.1 mV). We conclude that the modified method represents a simplified and equally effective approach to discriminate CF patients from non-CF subjects. Moreover, this method presents practical advantages for the patients related to hygiene and convenience, favoring its application in small children.