Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Initially, Cl^- conductance in the sweat duct was discovered to be impaired in CF, a finding that has been extended to all CFTR-expressing cells^,,. Subsequent cloning of the gene^, showed that CFTR functions as a cyclic-AMP-regulated Cl^- channel; and some CF-causing mutations inhibit CFTR Cl^- channel activity^,,,. The identification of additional CF-causing mutants with normal Cl^- channel activity indicates, however, that other CFTR-dependent processes contribute to the disease. Indeed, CFTR regulates other transporters^,, including Cl^--coupled HCO^-₃ transport^,. Alkaline fluids are secreted by normal tissues, whereas acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity. HCO^-₃ and pH affect mucin viscosity^, and bacterial binding^,. We have examined Cl^--coupled HCO^-₃ transport by CFTR mutants that retain substantial or normal Cl^- channel activity. Here we show that mutants reported to be associated with CF with pancreatic insufficiency do not support HCO^-₃ transport, and those associated with pancreatic sufficiency show reduced HCO^-₃ transport. Our findings demonstrate the importance of HCO^-₃ transport in the function of secretory epithelia and in CF.