Hypoxia-adenosinergic suppression and redirection of the immune response has been implicated in the regulation of antipathogen and antitumor immunity, with hypoxia-inducible factor 1α (HIF-1α) playing a major role. In this study, we investigated the role of isoform I.1, a quantitatively minor alternative isoform of HIF-1α, in antibacterial immunity and sepsis survival. By using the cecal ligation and puncture model of bacterial peritonitis, we studied the function of I.1 isoform in T cells using mice with total I.1 isoform deficiency and mice with T-cell-targeted I.1 knockdown. We found that genetic deletion of the I.1 isoform resulted in enhanced resistance to septic lethality, significantly reduced bacterial load in peripheral blood, increased M1 macrophage polarization, augmented levels of proinflammatory cytokines in serum, and significantly decreased levels of the anti-inflammatory cytokine IL-10. Our data suggest a previously unrecognized immunosuppressive role for the I.1 isoform in T cells during bacterial sepsis. We interpret these data as indicative that the activation-inducible isoform I.1 hinders the contribution of T cells to the antibacterial response by affecting M1/M2 macrophage polarization and microbicidal function.