Heparin binding to serum proteins and their subsequent precipitation is reportedly increased in cystic fibrosis (CF). We have confirmed this finding for CF patients over the age of 12 [11.34 +/- 2.42 mg/ml precipitated protein for normals (n = 19) versus 17.46 +/- 4.60 mg/ml for CF patients (n = 37), P less than 0.001; 0.629 +/- 0.098 mg/ml precipitated heparin for normals versus 0.789 +/- 0.206 for CF patients, P less than 0.01]. We have also shown that patients with a variety of pulmonary diseases unrelated to CF do not show this effect. When the amounts of protein and heparin precipitated are compared with the amount of IgG found in the whole serum sample, the correlation coefficients (protein r = 0.77; heparin, 0.74; n = 81) are significant at a level of P less than 0.001. In addition, the report that young CF patients exhibit hypogammaglobulinemia prompted us to examine serum samples from CF patients and age-matched controls under the age of 12. No differences were found. To investigate the molecular basis for this effect, sera from patients with CF and from age-matched controls were precipitated with 50 mg% heparin at pH 5.57. Pellets resolubilized in 8 M urea were fractionated on DEAE-Sephadex and analyzed by double-immunodiffusion, SDS-PAGE, immunoelectrophoresis, and radial immunodiffusion. IgG constituted 55-56% of the eluted protein. When serum from all donors was fractionated by Staph A-Sepharose into IgG and non-IgG fractions, 85-89% of heparin precipitable protein was in the IgG fraction.