Mice with a targeted gene disruption of p85 alpha, a regulatory subunit of phosphoinositide 3-kinase, had impaired B cell development at the pro-B cell stage, reduced numbers of mature B cells and peritoneal CD5(+) Ly-1 B cells, reduced B cell proliferative responses, and no T cell-independent antibody production. These phenotypes are nearly identical to those of Btk(-/-) or rid (X-Linked immunodeficiency) mice. These results provide evidence that p85 alpha is functionally Linked to the Btk pathway in antigen receptor-mediated signal transduction and is pivotal in B cell development and functions.