T cell proliferation in vivo is presumed to reflect a T cell receptor (TCR)-mediated polyclonal response directed to various environmental antigens. However, the massive proliferation of T cells seen in viral infections is suggestive of a bystander reaction driven by cytokines instead of the TCR. In mice, T cell proliferation in viral infections preferentially affected the CD44^hi subset of CD8⁺ cells and was mimicked by injection of polyinosinic-polycytidylic acid [poly(I:C)], an inducer of type I interferon (IFN I), and also by purified IFN I; such proliferation was not associated with up-regulation of CD69 or CD25 expression, which implies that TCR signaling was not involved. IFN I [poly(I:C)]-stimulated CD8⁺ cells survived for prolonged periods in vivo and displayed the same phenotype as did long-lived antigen-specific CD8⁺ cells. IFN I also potentiated the clonal expansion and survival of CD8⁺ cells responding to specific antigen. Production of IFN I may thus play an important role in the generation and maintenance of specific memory.