More than 250 mutations have been detected in the cystic fibrosis (CF) transmembrane regulator (CFTR) gene, most of which are single point mutations or small deletions or insertions of a few nucleotides. Here we report the first large deletion identified in the CFTR gene, which involves 50 kb in two stretches of DNA: one of 10 kb from exon 4 to exon 7, and another of 40 kb, spanning exons 11 to 18. The deletion has been detected via uniparental inheritance of CFTR microsatellite alleles (IVS17BTA and IVS17BCA) in 3 independent CF families. Clinical status of the 3 CF patients, of which two have the delta F508 mutation as the other CF allele, suggests that this mutation is responsible for a severe clinical phenotype, indistinguishable from homozygous delta F508 patients. The deletion detected here suggests that other large, but less complex molecular defects could also exist in the CFTR gene.