The rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry) is critical for complement homeostasis. Gene deletion is 100% embryonically lethal; Crry-deficient (Crry-/-) mice were rescued by back-crossing onto C3 deficiency, confirming that embryo loss was complement mediated. In order to rescue viable Crry-/- mice without deleting C3, we have tested inhibition of C5 during gestation. Crry+/- females were given neutralizing anti-C5 mAb immediately prior to mating with Crry+/- males and C5 inhibition maintained through pregnancy. A single, healthy Crry-/- female was obtained and mating with Crry+/- males yielded healthy litters containing equal numbers of Crry+/- and Crry-/- pups. Inter-crossing Crry-/- mice yielded healthy litters of expected size. Although the mice were not anemic, exposure of Crry-/- erythrocytes to normal mouse serum caused C3 deposition and lysis, while transfusion into normal or C6-/- mice resulted in rapid clearance. Complement activity and C3 levels in Crry-/- mice were markedly reduced. Comparison with factor H deficient (CfH-/-) mice revealed similar levels of residual C3; however, unlike the CfH-/- mice, Crry-/- mice showed no evidence of renal injury, demonstrating distinct roles for these regulators in protecting the kidney.