In addition to the tyrosines of the Ig alpha and beta immunoreceptor tyrosine-based activation motifs (ITAMs), the evolutionarily conserved Ig alpha non-ITAM tyrosine 204 becomes phosphorylated upon antigen recognition by the B cell receptor (BCR). Here we demonstrate that splenic B cells from mice with a targeted mutation of Ig alpha Y204 exhibited an isolated defect in T cell-independent B cell activation, proliferation, and antibody response upon BCR engagement, yet normal BCR capping, antigen internalization, antigen presentation, and T cell-dependent antibody production. Mutant B cells, present in normal numbers, exhibited unimpaired BCR-induced spleen tyrosine kinase (Syk) phosphorylation but reduced B cell linker protein (BLNK) phosphorylation, calcium flux, and nuclear factor kappa B (NF kappa B), c-jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. These results suggest that Ig alpha non-ITAM tyrosine 204 promotes a distinct cellular response, namely T-independent B cell proliferation and differentiation via phosphorylation of the adaptor BLNK.