Defective sperm-egg recognition is recognized as one of the major causes of failed fertilization in IVF programs. Our recent findings have revealed that defects in sperm-zona pellucida (ZP) interaction are linked to an under-representation of the molecular chaperone, heat shock protein A2 (HSPA2), owing to its ability to participate in sperm surface remodeling. To determine the mechanisms responsible for reduced HSPA2 expression, the current study aimed to explore the sensitivity of this chaperone to oxidative stress. These studies were performed both by inducing oxidative stress in vitro through the treatment of normal spermatozoa with hydrogen peroxide (H2O2) or the cytotoxic lipid aldehyde 4-hydroxynonenal (4HNE) and by examining the presence of markers of oxidative stress in the spermatozoa of IVF patients with known ZP-binding defects. Our results revealed that the ability of human spermatozoa to interact with homologous ZP was significantly (p<0.01) disrupted following both 4HNE and H2O2 treatment. Upon investigating the mechanism of action, it was demonstrated that oxidative stress targeted HSPA2 for covalent modification by 4HNE. These data raise the possibility that 4HNE adduction of HSPA2 may cause attenuation of its chaperone activity and a subsequent dysregulation of its ability to remodel the sperm surface in preparation for ZP binding. Examination of markers of oxidative stress in the spermatozoa of IVF patients with severely reduced HSPA2 protein levels revealed an unexpected loss of 4HNE and ubiquitin adducts in the protein lysate. Marked differences in global protein content were also observed in these lysates compared to those obtained from the spermatozoa of healthy donors. In view of these data, further work is now being conducted to determine whether oxidative stress and the resultant adduction reactions between lipid aldehydes and their target proteins may in turn signal vulnerable sperm proteins for ubiquitination and subsequent destruction by the proteasome complex.