Beryllium metal and its salts can produce disease in man and in animal models. Beryllium disease is thought to involve cell-mediated immunity and an antigen-dependent response by beryllium-specific T cells. Beryllium salts have been shown to stimulate lymphocyte proliferation and release of lymphokines, and to induce granuloma formation and delayed-type hypersensitivity reactions in mice, guinea pigs and man. The studies described here were designed to test the hypothesis that a second lymphocyte population, B cells, may be responding nonspecifically to beryllium. Different populations of BDF₁ mouse lymphocytes were cultured in the presence of varying concentrations of beryllium sulfate (BeSO₄), and the increase in 125-iodouracildeoxyriboside uptake after 72 h in culture was determined. The data show that BeSO₄ is weakly mitogenic for normal mouse spleen cells. Furthermore, BeSO₄ is mitogenic for normal and nude mouse spleen B cells and not for spleen T cells or thymocytes in vitro. These findings suggest that BeSO₄ can stimulate B cells nonspecifically, and support the hypothesis that polyclonal activation of B cells by beryllium may occur.