Classic Hodgkin lymphoma (cHL) is one of the most common pediatric solid tumors and is responsible for cancer-related deaths in children. Therefore, to modulate the active antitumor T-cell immune response in cHL can be a treatment strategy. In the present study, we aimed to investigate the expression profiles of selected antitumor immune response genes in pediatric cHL and their relationships with clinical and prognostic parameters to determine their significance in precision medicine. Thirty-nine pediatric nodal cHL patients were enrolled in the study. We analyzed mRNA expression of selected immune response regulatory genes such as PD-L1, CSF2, CTLA4, CXCL5, IDO1, CXCL8, MIF, NOS2, PDCD1, PTGS2, and TGF beta 1 using real-time quantitative polymerase chain reaction. Only PD-L1 overexpression was statistically related to bulky disease, advanced tumor stage, and high-risk disease category and seen significantly in Epstein-Barr virus-negative pediatric cHL. No expression profiles were correlated with relapse or survival. We conclude that PD-L1 overexpression in pediatric cHL cases is a strong predictor of high-risk categorization. In addition to being a prognostic biomarker, PD-L1 blockade is also a druggable marker for the targeted therapy in Epstein-Barr virus-negative pediatric Hodgkin lymphoma.