AbstractFollicular helper T (T_FH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate T_FH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying T_FH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human T_FH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs T_FH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of T_FH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.