An assessment of beta cell and exocrine pancreatic reserve based on fasting C peptide and immunoreactive trypsin (IRT) concentrations was carried out in non-diabetic (fasting blood glucose less than 6 mmol/l) patients with cystic fibrosis (CF; n = 20) and their parents (heterozygotes; n = 26). These indices were also measured in comparable control subjects (n = 20) and insulin-dependent diabetics (IDDs). C peptide concentrations in 18 CF patients were markedly lower than those in controls, and in 18 were comparable to those in IDDs (n = 27). Fasting C peptide concentration in heterozygotes was also significantly lower than that in controls and was significantly greater than that in IDDs. IRT concentrations in CF patients and heterozygotes were also significantly lower than those in controls. The frequency of subnormal C peptide concentrations was greater in CF patients with non-measurable IRT than in those who had residual IRT in their sera. These data show for the first time that the diminution in beta cell reserve in CF patients may be of a magnitude similar to that in IDDs in spite of their normal blood glucose and HbA1 concentrations. Therefore, these patients may have enhanced insulin sensitivity. CF heterozygotes too have a significant diminution in endocrine and exocrine pancreatic reserve when compared with the controls.