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Clinical use of immune-checkpoints inhibitors (anti PD-1/PD-L1) resulted very effective for the treatment of relapsed/refractory classic Hodgkin Lymphoma (CHL). Recently, T cell Ig and ITIM domains (TIGIT) has been recognized as an immune checkpoint receptor able to negatively regulate T cell functions. Herein, we investigated the expression of TIGIT in CHL microenvironment in order to find a potential new target for inhibitor therapy. TIGIT, PD-1 and PD-L1 expression was evaluated in 34 consecutive patients with CHL. TIGIT expression in T lymphocytes surrounding Hodgkin Reed-Sternberg (HRS) cells was observed in 19/34 patients (56%), of which 11 (58%) had advanced stages. In 16/19 (84%) cases, TIGIT+ peritumoral T lymphocytes showed also PD-1 expression. All 15 TIGIT− patients had PD-L1 expression in HRS cells (100%) while among 19 TIGIT+ patients, 11 (58%) were PD-L1+ and 8 (42%) were PD-L1−. Using a new scoring system for TIGIT immunoreactivity, all TIGIT+ cases with higher score (4/19) were PD-L1−. Our results confirm co-expression of TIGIT and PD-1 in peritumoral T lymphocytes. Of relevance, we demonstrated a mutually exclusive expression of TIGIT and PD-L1 using new TIGIT scoring system able to identify this immunocheckpoints’ modulation. These results pave the way to new therapeutic strategies for relapsed/refractory CHL.