Protection against influenza is mediated by neutralizing antibodies, and their induction at high and sustained titers is key for successful vaccination. Optimal B cells activation requires delivery of help from CD4⁺ T lymphocytes. In lymph nodes and tonsils, T-follicular helper cells have been identified as the T cells subset specialized in helping B lymphocytes, with interleukin-21 (IL-21) and inducible costimulatory molecule (ICOS1) playing a central role for this function. We followed the expansion of antigen-specific IL-21⁺ CD4⁺ T cells upon influenza vaccination in adults. We show that, after an overnight in vitro stimulation, influenza-specific IL-21⁺ CD4⁺ T cells can be measured in human blood, accumulate in the CXCR5⁻ICOS1⁺ population, and increase in frequency after vaccination. The expansion of influenza-specific ICOS1⁺IL-21⁺ CD4⁺ T cells associates with and predicts the rise of functionally active antibodies to avian H5N1. We also show that blood-derived CXCR5⁻ICOS1⁺ CD4⁺ T cells exert helper function in vitro and support the differentiation of influenza specific B cells in an ICOS1- and IL-21–dependent manner. We propose that the expansion of antigen-specific ICOS1⁺IL-21⁺ CD4⁺ T cells in blood is an early marker of vaccine immunogenicity and an important immune parameter for the evaluation of novel vaccination strategies.