The ability of heterologous prime-boost vaccination to elicit robust CD8⁺ T cell responses has been well documented. In contrast, relatively little is known about how this immunotherapeutic strategy impacts the functional qualities of expanded T cells in the course of effector and memory responses. Using vesicular stomatitis virus (VSV) as a boosting vector in mice, we demonstrate that a massive secondary expansion of CD8⁺ T cells can be achieved shortly after priming with recombinant adenoviral vectors. Importantly, VSV-boosted CD8⁺ T cells were more potent than those primed by adenoviruses only, as measured by cytokine production, granzyme B expression, and functional avidity. Upon adoptive transfer, equivalent numbers of VSV-expanded CD8⁺ T cells were more effective (on a per-cell basis) in mediating antitumor and antiviral immunity than T cells only primed with adenoviruses. Furthermore, VSV boosting accelerated the progression of expanded CD8⁺ T lymphocytes to a central memory phenotype, thereby altering the effector memory profile typically associated with adenoviral vaccination. Finally, the functional superiority of VSV-expanded T cells remained evident 100 d after boosting, suggesting that VSV-driven immunological responses are of sufficient duration for therapeutic applications. Our data strongly support the choice of VSV as a boosting vector in prime-boost vaccination strategies, enabling a rapid amplification of CD8⁺ T cells and improving the quality of expanded T cells during both early and late immunological responses.