The Complement Factor B gene (CFB) of the alternative complement pathway has been identified in the sheep Major Histocompatibility Complex (MHC) and its genomic sequence determined. CFB is located approximately 600 bp upstream of the complement C2 gene, contains 18 exons, and manifests the domain signature characteristic of CFB protein. Thirteen single nucleotide polymorphisms were identified in merino sheep and interbreed variation was identified by comparison with International Sheep Genomics Consortium data. Two predicted non synonymous substitutions were observed and in-silico analysis indicates that these are likely to have a destabilizing effect on the protein structure. Sheep and cattle CFB were compared and shown to contain a common nine nucleotide deletion in exon 18 relative to human CFB. Predicted CFB amino acid sequences for these two species contain 761 aa relative to 764 aa in the human orthologue. Sequencing of the cosmid and BAC clones used in this study permitted the relative positions of three adjacent loci to be determined and showed that the previously described microsatellite locus (BfMs) is located within SKIV2L.