Bis (Bcl-2 interacting cell death suppressor), also known as Bag3 or CAIR-1, is involved in anti-stress and anti-apoptotic pathways. In addition to Bcl-2, Bis binds to several proteins, suggesting it has diverse functions in normal and pathological conditions. To better define the physiological function of Bis in vivo, we developed bis-deficient mice using a cre-loxP system. Targeted disruption of exon 4 of the bis gene was demonstrated by Southern blotting and PCR, and Western blotting showed that no intact or truncated Bis protein was synthesized in bis^-/- mice. While heterozygotes were fertile and appeared normal, Bis-deficient mice showed growth retardation and died by 3 weeks after birth. The relative weight of the thymus and spleen was reduced and the total number of white blood cells, splenocytes and thymocytes were significantly reduced compared to wild-type littermates. Serum profiles indicated that significant hypoglycemia as well as decrease in triglyceride and cholesterol levels. Expression profiles of metabolic genes indicated that gluconeogenesis and -oxidation are activated in the liver of bis^-/- mice. This activation, as well as a decrease in peripheral fat and an induction of fatty liver, appears to be an adaptive response to hypoglycemia. Our study reveals that absence of Bis has considerable influences on postnatal growth and survival, possibly due to a nutritional impairment.