Antigen‐stimulated B lymphocytes either differentiate into IgM‐secreting plasma cells or into memory B cells that secrete other immunoglobulin isotypes upon antigen restimulation. The mechanisms that generate and maintain memory B cells are poorly understood. Previously, we described a severe B lymphocyte deficiency in adult strain A/WySnJ mice compared to subline A/J. Here we show that the single, autosomal co‐dominant locus responsible for the deficiency also diminishes IgG‐secrcting B cell formation without interfering with IgM‐secreting plasma cell differentiation. A/WySnJ secondary IgG₁ responses to the protein antigens hemocyanin, bovine γ‐globulin, ovalbumin, lysozyme and β‐galactosidase were 6‐ to 50‐fold lower than A/J responses. The defect also decreased secondary IgG_2a and IgG₃ responses, and primary IgG₁ and IgG_2a responses. The reduced A/WySnJ secondary IgG₁ response was not due to differential response kinetics or dose responsiveness, and could not be augmented to A/J levels by repeated immunizations. Serum IgG₁, IgG_2a and IgG₃ levels from nonimmune A/WySnJ mice were similarly reduced. The secondary IgG₁ response and splenic B cell percentage showed significant positive correlation (r = 0.72) in F₂ mice, suggesting that a single locus controlled both traits. In contrast, A/WySnJ mice made good primary IgM responses to hemocyanin, β‐galactosidase, and the thymus‐independent antigen trinitrophenyl‐Ficoll. The A/WySnJ splenic adherent cells were competent in antigen‐presenting function, and A/WySnJ immune T cells proliferated in response to antigen and provided the requisite B cell stimulatory signals for an IgG₁ response. Together, our results suggest that A/WySnJ mice have a genetic lesion that causes a selective IgG immune response dysfunction. The absence of IgG‐secreting cell precursors or a defect in precursor activation or differentiation are two possible mechanisms which could precipitate a selective IgG response dysfunction. We propose that the defective A/WySnJ and normal A/J strain pair offer the opportunity to use a natural genetic variation as a tool to investigate B lymphocyte development and function.