Mitochondrial protein p13 is widely expressed in central and peripheral tissues. We previously showed p13 knockout mice with C57BL/6 genetic background (p13-KO/B6 mice) showed several phenotypic changes including a severe early postnatal mortality. Here, we examined the effects of genetic background (C57BL/6, BALB/c, or ICR) on the phenotypic changes of p13-KO mice. Whereas more than half of p13-KO/B6 mice died during the first postnatal day (P0), more than half of p13-KO mice survived the day under a BALB/C or an ICR genetic background. At P0, p13-KO mice with all three genetic background showed significant underweight and hypoglycemia. Interestingly, approximately 10% of p13-KO/BALB and p13-KO/ICR but not p13-KO/B6 mice exhibited a blood clot on their top of the head, which is deeply associated with their mortality. Accordingly, these data suggest that p13 is important for early postnatal survival, which could be modulated by their genetic background.