Background Tumor microenvironment, specifically tumor-associated macrophages, plays an important role in tumor initiation and progression. CD163 has been recognized as a valuable specific macrophage marker. Cyclooxygenase-2 (Cox2) plays a role in tumor progression. CD31 is reliable for estimation of the density of microvesseles (MVD), which has prognostic importance in several malignant tumors. Thus, the current study was conducted to test the association between CD163, Cox2, and CD31 expression with the prognosis of classical Hodgkin lymphoma (cHL) patients and their potential correlation with clinicopathological variables. Method CD163, Cox2, and CD31 expressions were examined in newly diagnosed patients with cHL through immunohistochemistry on tissue biopsy and the results were correlated with the patients’ outcome after the median follow-up, which was about 35 months. Results 104 patients were included in this study. High CD163 was found in 32.7% of the patients. Cox2 was positive in 42.3% of them. CD 31 with high MVD (≥10%) was found in 51% of the subjects. A significant association was detected between CD163 and Cox2 with tumor stage (P = 0.001, and P = 0.001) and IPS score. Regarding CD31, we could not find any significant associations with disease parameters, except with histological subtype (P = 0.001). A significant relationship was observed between Cox2 and CD163 expression and the relapse rate (P = 0.001, P = 0.01, respectively). Regarding survival, only Cox2 showed a significant association with disease-free survival (P = 0.0379). Conclusion These findings suggested that Cox2 and …