The mature B cell compartment of MHC class II–deficient B6 I-Aα^−/− and the btk-defective CBA/N mouse strain is 4- to 5-fold smaller than in wild-type B6 mice. The defect in B6 I-Aα^−/− mice is intrinsic to B cells and due to a 4- to 5-fold reduced lifespan, which however can be normalized by an I-Eα^d transgene, but only when expressed early during B cell development. The reduced number of mature B cells in the btk-defective CBA/N mouse is due to a 4- to 5-fold lower number of immature splenic B cells entering the mature compartment. The combined defects of reduced lifespan and impaired generation in double mutant mice result in a severe deficiency in the mature B cell pool.