P. vivax and P. falciparum parasites display different tropism for host cells and induce very different clinical symptoms and pathology, suggesting that the immune responses required for protection may differ between these two species. However, no study has qualitatively compared the immune responses to P. falciparum or P. vivax in humans following primary exposure and infection. Here, we show that the two species differ in terms of the cellular immune responses elicited following primary infection. Specifically, P. vivax induced the expansion of a subset of CD8(+) T cells expressing the activation marker CD38, whereas P. falciparum induced the expansion of CD38(+) CD4(+) T cells. The CD38(+) CD8(+) T cell population that expanded following P. vivax infection displayed greater cytotoxic potential compared to CD38(-) CD8(+) T cells, and compared to CD38(+) CD8(+) T cells circulating during P. falciparum infection. We hypothesize that P. vivax infection leads to a stronger CD38(+) CD8(+) T cell activation because of its preferred tropism for MHC-I-expressing reticulocytes that, unlike mature red blood cells, can present antigen directly to CD8(+) T cells. This study provides the first line of evidence to suggest an effector role for CD8(+) T cells in P. vivax blood-stage immunity. It is also the first report of species-specific differences in the subset of T cells that are expanded following primary Plasmodium infection, suggesting that malaria vaccine development may require optimization according to the target parasite.