Interactions between 4‐1BB and its ligand, 4‐1BBL, enhance CD8⁺ T cell‐mediated antiviral and antitumor immunity in vivo. However, mechanisms regulating the priming of CD8⁺ T cell responses by 4‐1BB remain unclear, particularly in humans. The 4‐1BB receptor was undetectable on naive or resting human CD8⁺ T cells and induced in vitro by TCR triggering. Naive cord blood cells were therefore primed in vitro against peptides or cellular antigens and then co‐stimulated with 4‐1BBL or agonistic antibodies. Co‐stimulation enhanced effector function such as IFN‐γ production and cytotoxicity by augmenting numbers of antigen‐specific and effector CD8⁺ T cells. OKT3 responses also showed reduced cell death and revealed that the proliferation of CD8⁺ T cells required two independently regulated events. One, the induction of IL‐2 production, could be directly triggered by 4‐1BB engagement on CD8⁺ T cells in the absence of accessory cells. The other, expression of CD25, was induced with variable efficacy by accessory cells. Thus, suboptimal accessory cells and 4‐1BB co‐stimulation combined their effects to enhance IL‐2 production and proliferation. Reduced apoptosis observed after co‐stimulation in the presence of accessory cells correlated with increased levels of Bcl‐X_L in CD8⁺ T cells, while Bcl‐2 expression remained unchanged. Altogether, 4‐1BB enhanced expansion, survival and effector functions of newly primed CD8⁺ T cells, acting in part directly on these cells. As 4‐1BB triggering could be protracted from the TCR signal, 4‐1BB agonists may function through these mechanisms to enhance or rescue suboptimal immune responses.