The role of the invariant chain (Ii), an MHC class II-associated chaperone, in B cell development is controversial. Ii deficient mice (Ii(-/-) mice) show a defect in B cell development. This defect has been attributed to the absence of a fragment liberated from the Ii by intramembranous proteolysis. It was proposed that this fragment is required for activation of the NF-kappaB pathway as a means of controlling B cell maturation. The opposing view holds that defects in the assembly of MHC class II molecules result in impaired B cell development. Here we demonstrate that a lack of Ii indeed causes defects in B cell development, with fewer mature B cells in the periphery as previously reported, but that in a compound-mutant from which both Ii and all MHC class II subunits are absent, B cell development is normal. We suggest that neither Ii itself, nor the MHC class II products are required for normal B cell development.