Secretory component (SC or the poly-Ig receptor) plays a crucial role in mucosal immunity by translocating polymeric IgA and IgM through secretory epithelial cells into external body fluids. Labeled restriction fragments from human SC cDNA were used to screen a human genomic leukocyte library. Three overlapping clones, spanning a total of 19 kb of the human SC gene, including 3 kb of the 5' flanking region, were characterized. The putative TATA box candidate, preceded by a CAAT-like box, was found 329 nucleotides upstream of the first exon. Altogether 11 exons covering the entire coding region were identified. The exon size ranged from 59 to 657 nucleotides and exon-intron junctions followed known consensus sequences. Three of the five extracellular Ig-related domains (D1, D4 and D5) were confined to one exon each (E3, E5 and E6), whereas D2 and D3 were encoded by the same exon (E4). The latter exon corresponds to that involved in alternate splicing of rabbit SC. The membrane-spanning segment was confined to part of one exon (E8). The cytoplasmic tail was encoded by four exons (E8-E11), whose boundaries encompassed fairly well the structural determinants proposed to be responsible for intracellular sorting of SC in the rabbit. The polymorphic restriction site reported earlier for Pvu II was localized to the third intron.