We have generated mice null for IFN-β and report the diverse consequences of IFN-β for both the innate and adaptive arms of immunity. Despite no abnormalities in the proportional balance of CD4 and CD8 T cell populations in the peripheral blood, thymus, and spleen of IFN-β^-/- mice, activated lymph node and splenic T lymphocytes exhibit enhanced T cell proliferation and decreased tumor necrosis factor α production, relative to IFN-β^+/+ mice. Notably, constitutive and induced expression of tumor necrosis factor α is reduced in the spleen and bone marrow (BM) macrophages, respectively, of IFN-β^-/- mice. We also observe an altered splenic architecture in IFN-β^-/- mice and a reduction in resident macrophages. We identify a potential defect in B cell maturation in IFN-β^-/- mice, associated with a decrease in B220^+ve/high/CD43^-ve BM-derived cells and a reduction in BP-1, IgM, and CD23 expression. Circulating IgM-, Mac-1-, and Gr-1-positive cells are also substantially decreased in IFN-β^-/- mice. The decrease in the numbers of circulating macrophages and granulocytes likely reflects defective maturation of primitive BM hematopoiesis in mice, shown by the reduction of colony-forming units, granulocyte-macrophage. We proceeded to evaluate the in vivo growth of malignant cells in the IFN-β^-/- background and give evidence that Lewis lung carcinoma-specific tumor growth is more aggressive in IFN-β^-/- mice. Taken altogether, our data suggest that, in addition to the direct growth-inhibitory effects on tumor cells, IFN-β is required during different stages of maturation in the development of the immune system.