Aims: Classic Hodgkin lymphoma (cHL) should be distinguished from its wide variety of histological mimics, including reactive conditions and mature B and T cell neoplasms. Thymus and activation‐related chemokine (TARC) is produced in extremely high quantities by the Hodgkin/Reed–Sternberg (HRS) tumour cells and is largely responsible for the attraction of CD4+ T cells into the cHL tumour micro‐environment. In the current study we evaluated the diagnostic potential of TARC immunohistochemistry in daily practice in a tertiary referral centre in the Netherlands. Methods and results: A total of 383 cases, approximately half of which were cHL mimics, were prospectively evaluated in the period from June 2014 to November 2020. In 190 cHL cases, 92% were TARC‐positive and the majority of cases showed strong and highly specific staining in all HRS cells (77%). In most cases, TARC could discriminate between nodular lymphocyte‐predominant and lymphocyte‐rich Hodgkin lymphoma. HRS‐like cells in mature lymphoid neoplasms were rarely positive (6.4%) and there was no TARC staining at all in 64 reactive lymphadenopathies. Conclusions: TARC immunohistochemistry has great value in differentiating between cHL and its mimics, including nodular lymphocyte‐predominant Hodgkin lymphoma, reactive lymphadenopathies and mature lymphoid neoplasms with HRS‐like cells. [ABSTRACT FROM AUTHOR]