Follicular helper T cells (T_FH cells) constitute the CD4⁺ T cell subset that is specialized to provide help to germinal center (GC) B cells and, consequently, mediate the development of long-lived humoral immunity. T_FH cell differentiation is driven by the transcription factor Bcl6, and recent studies have identified cytokine and cell–cell signals that drive Bcl6 expression. However, although T_FH dysregulation is associated with several major autoimmune diseases, the mechanisms underlying the negative regulation of T_FH cell differentiation are poorly understood. In this study, we show that STAT5 inhibits T_FH cell differentiation and function. Constitutive STAT5 signaling in activated CD4⁺ T cells selectively blocked T_FH cell differentiation and GCs, and IL-2 signaling was a primary inducer of this pathway. Conversely, STAT5-deficient CD4⁺ T cells (mature STAT5^fl/fl CD4⁺ T cells transduced with a Cre-expressing vector) rapidly up-regulated Bcl6 expression and preferentially differentiated into T_FH cells during T cell priming in vivo. STAT5 signaling failed to inhibit T_FH cell differentiation in the absence of the transcription factor Blimp-1, a direct repressor of Bcl6 expression and T_FH cell differentiation. These results demonstrate that IL-2, STAT5, and Blimp-1 collaborate to negatively regulate T_FH cell differentiation.