Hodgkin lymphoma (HL) has become one of the most curable hematological neoplasia. Clinical and biological factors remain the main pillars guiding therapeutic strategies in HL. Recent studies have improved our understanding of the phenotype, the characteristics of histogenesis, and other possible mechanisms of lymphomagenesis, including the role of Epstein-Barr virus (EBV) infection. Tumor cells manipulate the microenvironment, allowing them to develop their malignant phenotype and evade the attack of the host’s immune response so that the interaction between tumor cells and the reactive microenvironment determines not only the histological features but also the clinical-pathological characteristics and prognosis of these patients – essential for the development of future therapies targeting various other cellular components of the tumor microenvironment. This article aimed to evaluate the characteristics of the tumor microenvironment and malignant cells using histopathology and immunohistochemistry (IHC) techniques to highlight the association of EBV and to study the expression of characteristic antigens in malignant and non-malignant cells within the tumor mass (overexpression of BCL2 (B-cell lymphoma 2) in malignant cells, presence of PD1 (Programmed cell death Protein 1) on T lymphocytes, CD68+ macrophages in the tumor microenvironment, and presence of EGFR (epidermal growth factor receptor). The analysis of the data collected in this paper highlights several key parameters with prognostic value and statistical significance: the EBV infection at diagnosis, its association with low-intensity BCL2(+), the presence of CD68 with rosette formation, and the identification of specific vascularization patterns. The development of prognostic systems that take into account the integration of biological prognostic markers seems essential for a better risk stratification.