Increasing paternal age in developed countries over the past 40 years raised the question of how aging affects reproductive success. Oxidative stress, which is defined as a net increase of reactive oxygen species within the cell because of an increase in ROS formation and/or a decrease in antioxidant protection, is associated with male infertility^1,2,3. There is rising concern regarding the relationship between paternal age and developmental, neurological and behavioral/mental disorders in the offspring^4,5,6. Peroxiredoxins (PRDXs) are newly discovered antioxidant enzymes which are considered as major players in the antioxidant protection of human spermatozoa^7,8. Spermatozoa from infertile men have high levels of DNA damage and impaired motility that are associated with low levels of PRDXs, particularly PRDX6⁹. We hypothesize that the absence of PRDX6 impairs male reproduction, which is worsen with age. Our objective was to investigate the impact of paternal aging on the integrity of sperm nucleus and reproductive success of Prdx6-null males. Two-, 8- or 20-month-old Prdx6-null males and their wild type controls were used to determine DNA fragmentation levels (DFI) using Sperm Chromatin Structure Assay, DNA compaction by high DNA stainability (HDS) and level of free thiols and of protamination by monobromobimane (mBBr) or chromomycin A3 (CMA3) labeling by flow cytometry, DNA oxidation by 8-hydroxy-2' -deoxyguanosine (8-OHdG) levels by immunocytochemistry along with sperm motility, cytoplasmic droplet retention rates and number of pups and litters per male. The absence of PRDX6 caused age-dependent decrease of sperm motility and increase of cytoplasmic droplet retention rate compared to wild type controls. Prdx6-null mice showed increased DFI and of HDS, CMA3 and mBBr-labeling, suggesting higher DNA fragmentation and lower DNA condensation, respectively compared to wild type controls. Moreover, we observed increased sperm DNA oxidation in the Prdx-null males compared to their wild type controls. At 8 and 20 months of age, Prdx6-null males showed lower motility, increased cytoplasmic droplet retention rate, DNA fragmentation and oxidation and lower DNA compaction (HDS) than young Prdx6-null and age-matched wild type males. Reproductive outcomes were significantly lower in Prdx6-null males compared to wild type controls and worsen with age. In conclusion, advanced paternal age affects sperm chromatin integrity, epididymal sperm maturation and fertility more severely in the absence of PRDX6. These data suggest a protective role for PRDX6 in age-associated decline in the sperm quality and its potential utility as biomarker for male fertility in assisted reproductive technologies. Supported by CIHR, FRQS and RQR-CREATE.