Mediastinal gray zone lymphoma (MGZL) represents a range of tumors possessing characteristics of both nodular sclerosis classical Hodgkin lymphoma (NSHL) and mediastinal large B-cell lymphoma (MLBCL). Here we report two patients with MGZL. Patient 1 was a 30-year-old woman and patient 2 was a 22-year-old man. Both patients had a mediastinal mass, were initially diagnosed with NSHL and exhibited resistance to first-line chemotherapy. Re-biopsy of the relapsed tumors or the residual lesion was performed and based on the findings the tumors were diagnosed as MGZL. In patient 1, the morphological features of the tumor resembled those of NSHL, but the immunophenotypic features indicated MLBCL. In patient 2, the tumor was a composite lymphoma with both NSHL and MLBCL components. Both the patients received high-dose chemotherapy followed by autologous peripheral-blood stem-cell transplantation. Although there is an overlap in the biological and morphological features between NSHL and MLBCL, the therapeutic approaches to NSHL and MLBCL are quite different. The development of effective therapies for MGZL is therefore extremely critical.