Prior to acquiring a memory phenotype, antigen-activated CD8(+) T cells need to expand and then undergo a contraction phase. Utilizing two different antigenic stimuli, we provide evidence that the tumor necrosis factor receptors OX40 and CD30 integrate synergistic signals during the expansion phase to help maintain CD8(+) effectors. Thus, double deficiency in OX40 and CD30 leads to CD8(+) cell loss during expansion after immunization either with OVA or with murine CMV. Following their contraction, OX40- and CD30-deficient CD8(+) T cells persist normally in CMV-infected mice. In contrast, persistence after OVA challenge is dependent on OX40 and CD30. Collectively, our data define the important role of both OX40 and CD30 during CD8(+) T-cell activation, and show that long-term CD8 persistence after contraction is regulated not only by stimulatory receptors but also by the nature of the antigen or how the antigen is presented.