The metabolic basis of the autosomal recessive disease cystic fibrosis (CF) remains unidentified. Elevated levels of a serum protein in CF homozygotes and obligate heterozygotes have been described. As heterozygotes are clinically unaffected, any consistently observed abnormality in these individuals is a likely pointer to the aetiology of the disease. The gene for this serum protein, called cystic fibrosis (CF) antigen, has been mapped to chromosome 1. It is not the gene that is mutant in CF because this has since been assigned to chromosome 7 by cosegregation of the disease with closely linked DNA markers in CF families. CF antigen is a product of normal and leukaemic granulocytes and is inducible in the promyelocytic cell line HL60 (M.N., J.D., C. Hayward, F. Northrop, D.J.H.B., J. Walker, V. van H. and D.S.S., manuscript in preparation). We have isolated cDNA clones for this protein from a library constructed with messenger RNA from chronic myeloid leukaemia (CML) cells. The complete nucleotide sequence was obtained from the cDNA clone and by primer extension of mRNA. We have confirmed that the gene encoding CF antigen is on chromosome 1 and have localized it to a particular region. RNA blot analysis shows a 550-bp major transcript in CML cells and in induced HL60. The amino-acid sequence predicted from the nucleotide sequence shows significant homology with intestinal and brain calcium-binding proteins. Abnormal accumulation of such a protein in CF is a clue which must be pursued now that evidence is gathering that the basic defect in CF is in pathways controlling chloride channel activity.