Among patients with cystic fibrosis (CF), those in the subset who develop hypergammaglobulinemia and circulating immune complexes often have relatively severe disease and a decreased likelihood of survival. Because Fc receptors have an important role in the removal of immune complexes and because defective Fc receptor function has been associated with inheritance of the histocompatibility antigens HLA DR2 and HLA DR3, we postulated that HLA DR2 and/or HLA DR3 might be genetic markers for this subset of patients with CF. However, in a group of 20 carefully documented patients with CF, we found no association of HLA DR2 or HLA DR3 with serum immunoglobulin, immune complex levels, or evidence of rapidly progressive disease.