Murine genomic and cDNA clones were isolated to ascertain the mechanisms accounting for previously recognized multiple forms of complement C2 and factor B mRNA and to analyze structural similarities with the corresponding human gene products (C2, 74% and B, 85%, amino acid identity). Like the human Bf gene, murine Bf and C2 each consist of 18 exons with similar intron-exon organizations. The murine C2 gene (20 kilobases) is more than three times the size of Bf (6 kilobases) due to the presence of large intronic segments separating the exons encoding the NH2-terminal binding and central (von Willebrand factor) domains. Evidence from cDNA clones shows that the two C2 transcripts are generated by an alternative splice at the donor site of exon 14 producing long and short C2 mRNA species that differ by 21 base pairs encoding a region within the binding pocket (amino acids 636-642 (GSTCKDH)) of the serine proteinase domain. Tissue-specific multiple factor B transcripts are generated by alternative transcriptional initiation. From the structure of these transcripts the predicted regulation of expression and rates of translation of B programmed by the short and long mRNA species may differ, but the polypeptides are identical. These data indicate that different molecular mechanisms account for the multiple forms of C2 and factor B mRNA and that the structure of the different transcripts predicts differences in function and expression of the respective gene products.