Both the B cell–surface trigger(s) and the intracellular molecular mechanism(s) of somatic hypermutation in immunoglobulin (Ig) variable region genes remain unknown, partly because of the lack of a simple and reproducible in vitro model. Here, we show that upon surface immunoglobulin cross-linking followed by coculture with activated cloned T cells, the Burkitt's lymphoma cell line BL2 is induced to mutate its IgVH gene. Repeated activation of BL2 cells increased the frequency of mutation. The in vitro–induced mutations, which do not affect the IgM constant region, are point mutations distributed over the entire VHDJH gene segment and do not show evidence of antigen-driven selection.