HE2 is a human epididymis specific sperm binding secretory protein expressed by SPAG11 gene (chromosome 8p23-p22), a 103aa protein adopts a typical antigenic pattern with a subacrosomal equatorial distribution on the sperm head, this localization of HE2 with Beta-defensins in the epithelial defense system of epididymal duct have developed mechanism to fight ascending infections, including local production of these antimicrobial peptides and proteins. The regionalized epididymal expression of the HE2 and its isoforms suggests that they exert their effects at different times in the controlled sequence of sperm modification, maturation, binding and a direct role in fertilization. HE2 represents 3 major isoforms, HE2-alpha, HE2-beta and HE2-gamma, all variants have a common 71 residue N terminus but various C termini, these variations at C termini is due to frame shifting deletions. Thus, identical sequences and deletion, start and stop points indicate that HE2 isoforms are derived from alternative splicing of 8 or more exons of a single gene and working towards common microbial defense and sperm maturation to acquire fertilizing ability. The human HE2 protein and its isoforms are 28% conserved A gene product of rat epididymal duct, BIN1B, has been suggested to represent the rat counterpart of human HE2 protein. As HE2, BIN1B also shows structural characteristics of beta-defensins. HE2 beta: The 2 beta isoforms encode proteins of 133aa( HE2 beta1) and 108aa (HE2 beta2). HE2 B1 contains the 6 cysteine beta-defensin motif located on exon 4 of SPAG11 gene, its shows antimicrobial activity and play a role in host defense in the genital tract. HE2B2 play a role in both contraception and treatment of sexually transmitted diseases. The B2 contains a potential glycosaminoglycan attachment site at amino acid 102.