CD46 is a member of the regulators of complement activation (RCA) family and serves to protect autologous cells from complement mediated lysis. The CD46 gene consists of 14 exons and extensive RNA splicing produces protein isoforms of different molecular weight. Predominant protein isoforms of 66 and 56 kDa arise from splicing in or out of exon 8 which encodes a region rich in serine, threonine and proline residues known to be heavily O-glycosylated. An inherited allelic polymorphism controls the relative expression of these isoforms in PBL and other tissues. This study has analysed an independent and overriding tissue specific regulation of CD46 splicing. Salivary gland and kidney produce RNA transcripts that preferentially include exon 8, giving rise to the 66 kDa protein species, while exon 8 is spliced out in brain tissue to give the 56 kDa protein. The cytoplasmic tail of CD46 is encoded by either exon 13 (CYT 1) or exon 14 (CYT 2). There is a preferential deletion of exon 13 from transcripts in salivary gland, kidney and brain to encode a protein containing cytoplasmic tail CYT 2. This preferential production of the CYT 2 tail is contrary to that seen on peripheral blood lymphocytes where equivalent expression of both CYT 1 and CYT 2 is observed. Our results suggest that while the splicing of exons within most cells is controlled by nucleotide sequences within or close to the CD46 gene (i.e. cis-regulation), splicing in tissues such as salivary gland, kidney and brain is regulated by trans-splicing factors encoded by another gene(s).