In addition to responding to specific antigen, CD8+ T-cells with a memory (CD44hi) phenotype undergo bystander proliferation when exposed to certain cytokines, notably type I interferons (IFN I), in vivo; such proliferation does not require T-cell receptor ligation. Since IFN I is unable to induce proliferation of purified CD44hi CD8+ cells in vitro, stimulation of these cells in vivo may reflect IFN I-dependent release of other cytokines. Evidence is presented that IFN I induces macrophages to synthesize IL-15 mRNA and that, at the protein level, IL-15 causes selective stimulation of CD44hi CD8+ (but not CD4+) cells, both in vitro and in vivo. This finding raises the possibility that synthesis of IL-15 during infection may induce bystander proliferation of memory-phenotype CD8+ cells.