Human mucin gene MUC5AC is clustered with MUC2, MUC5B and MUC6 on chromosome 11p15.5. We report here the full length cDNA sequence upstream of the repetitive region of human MUC5AC. We have also determined the sequence of its large central tandem repeat array. The 5'-region reveals high degree of sequence similarity with MUC2 and MUC5B and codes for 1336 amino acids organized into a signal peptide, four pro-von Willebrand factor-like D domains (D1, D2, D' and D3) and a short domain which connects to the central repetitive region. In the central region, 17 major domains have been identified. Nine code for cysteine-rich domains (Cys-domains 1-9) and exhibit high sequence similarity to the cysteine-rich domains described in the central region of MUC2 and MUC5B. Cys-domains 1-5 are interspersed by domains enriched with serine, threonine, and proline residues. Cys-domains 1-9 are interspersed by four domains (TR1-TR4) composed of various numbers of MUC5AC-type repeats. Southern-blot analyses reveal allelic variations both in length and nucleotide sequence. The length polymorphism which is due to variable numbers of tandem repeats is located in TR1 and TR4, whereas a mutation polymorphism detected with TaqI is located in Cys-domain 6. In this study, the organization of MUC5AC has been entirely elucidated showing extensive similarity to the other chromosome 11p15 MUC genes, particularly MUC5B, and providing additional arguments for common evolution from a single ancestral gene.