CD8(+) T cells play critical roles in immunosurveillance by killing malignant or virally infected cells. Interleukin 15 (IL-15) is a critical cytokine for promoting proliferation and the effector capacity of CD8(+) T cells, and has been used to support the growth of CD8(+) T cells in cellular therapies of neoplastic diseases. Recent studies have shown that IL-15, in synergy with other cytokines, such as IL-6, enhances the T-cell receptor (TCR)-independent proliferation and function of CD8(+) T cells. The aim of the present study was to investigate the role of BaF3-mb15-RAE cells in stimulating mouse CD8(+) T cells. BaF3 cells were cultured and B16F10 cells were grown in DMEM. MTT assay was used to detect the proliferation of CD8(+) T cells. Cells were analyzed using flow cytometry. The results showed that IL-15 synergistically acts with another T-cell stimulatory molecule, RAE1ɛ, to potently promote the proliferation of CD8(+) T cells, induce CD8(+) T-cell activation and enhance granzyme B and interferon-γ (IFN-γ) production in the absence of signaling via the TCR. Moreover, IL-15 in combination with RAE1ɛ resulted in a cooperative effect on CD8(+) T-cell-mediated cytotoxicity against B16F10 tumor cells. Thus, results of the present study showed that IL-15, in synergy with RAE1ɛ, enhances the TCR-independent effector function of CD8(+) T cells in vitro, which may be useful in the cellular immunotherapy of cancer.