IgA is found only in birds and mammals where it is the principal immunoglobulin class found in secretions, providing protection at mucosal surfaces. The structure of IgA in birds is different from that of marsupials and eutherians. The avian heavy-chain constant region of IgA (Ca) consists of four domains, while marsupial and eutherian Ca consists of three domains plus a hinge. Here we describe the cloning and characterization of the heavy chain of IgA from the short-beaked echidna, Tachyglossus aculeatus, and report that monotreme Ca is composed of three domains plus a hinge, making it similar to its therian counterparts. The amino acid sequence identity of echidna Ca is approximately 47% with the therians and 30% with birds. Phylogenetic analysis of the Ca sequences provides strong support for the Theria hypothesis, which proposes that monotremes diverged prior to the separation of marsupial and eutherians, and directly contradicts the results of the mitochondrial data, which support a "Marsupionta" relationship which has marsupials and monotremes closer to each other. The characterization of the heavy chain of IgA from monotremes, in conjunction with the recent description of monotreme IgG and IgE nucleotide sequence, confirms that the "second big bang" of immunoglobulin evolution predated the divergence of extant mammals.