T‐cell functions must be tightly controlled to keep the balance between vital proinflammatory activity and detrimental overactivation. MicroRNA‐146a (miR‐146a) has been identified as a key negative regulator of T‐cell responses in mice. Its role in human T cells and its relevance to human inflammatory disease, however, remains poorly defined. In this study, we have characterized miR‐146a‐driven pathways in primary human T cells. Our results identify miR‐146a as a critical gatekeeper of Th1‐cell differentiation processes acting via molecular mechanisms not uncovered so far. MiR‐146a targets protein kinase C epsilon (PRKCε), which is part of a functional complex consisting of PRKCε and signal transducer and activator of transcription 4 (STAT4). Within this complex, PRKCε phosphorylates STAT4, which in turn is capable of promoting Th1‐cell differentiation processes in human CD4⁺ T lymphocytes. In addition, we observed that T cells of sepsis patients had reduced levels of miR‐146a and an increased PRKCε expression in the initial hyperinflammatory phase of the disease. Collectively, our results identify miR‐146a as a potent inhibitor of Th1‐cell differentiation in human T cells and suggest that dysregulation of miR‐146a contributes to the pathogenesis of sepsis.