Follicular helper T (T-FH) cells are a specialized subset of CD4(+) T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of T-FH cell survival remains unclear. Here we report that T-FH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for T-FH cell survival. The deletion of GPX4 in T cells selectively abrogated T-FH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased T-FH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating T-FH homeostasis, which can be targeted to enhance T-FH cell function in infection and following vaccination. T follicular helper (T-FH) cells are important for the generation of effective antibody responses. Yu and colleagues find that T-FH cells are exceptionally sensitive to death by ferroptosis and that this process is regulated by the activity of the selenoenzyme GPX4.