X‐linked immunodeficient (Xid) mice carry a Bruton′s tyrosine kinase (Btk) mutation and exhibit a selective failure to produce antibodies against bacterial capsular polysaccharides. Studies in vitro point to a fundamental survival defect of Xid B cells after receptor cross‐linking by thymus‐independent type‐2 (TI‐2) antigen because B cells undergo apoptosis without proliferating. We describe results from a novel model, which we have used to investigate the impact of the Xid mutation on migration, proliferation and differentiation of B cells after polysaccharide immunization in vivo. Immunoglobulin knock‐in mice, in which a large proportion of B cells express transgene‐encoded receptors specific for (4‐hydroxy‐3‐nitrophenyl)‐acetyl (NP), were crossed with CBA/N mice. The male progeny contain NP‐specific Xid B cells, while the female progeny contain NP‐specific B cells with normal Btk. After immunization with the TI‐2 antigen NP‐Ficoll, NP‐specific Xid B cells migrate to the T zones and proliferate. Despite transient up‐regulation of blimp‐1 and survival beyond the time when terminal differentiation is normally underway, Btk‐defective B cells fail to differentiate to plasmablasts or germinal center cells. CD40 ligation partially restores their ability to form plasma cells in response to TI‐2 antigen.