Humans possess a single epididymal CRISP, called CRISP1. By contrast, mice produce two epididymal CRISPs, CRISP1 and CRISP4. As such, we hypothesized that the function of epididymal human CRISP1 will be equivalent to the combined function of CRISP1 and CRISP4 in the mouse. In order to define mouse epididymal CRISPs function, and thus the likely relevance of epididymal CRISPs to human fertility, we produced Crisp1/Crisp4 double knockout mouse model. Crisp1/Crisp4 homozygous null males are fertile, but sperm have compromised function. Computer assisted sperm analysis (CASA) revealed that epididymal CRISPs are necessary for mouse sperm to acquire the capacity for rapidly progressive motility. Sperm acrosome fluorescent staining showed that CRISPs affect sperm normal ability to undergo the progesterone-induced acrosome reaction in vitro and thus, likely normal acrosome reaction ability in vivo. Further, we have shown that with increased age, 23 weeks, double knockout mice epididymides contained significantly reduced sperm content and significant immune infiltrates compared to their wild type counterparts. Collectively these data show that epididymal CRISPs are required for full function and suggest they protect sperm against immune-mediated attack in epididymis.