The prognostic value of histologic classification and single histomorphologic parameters in Hodgkin disease has been widely debated in the literature. Whereas several former studies identified single parameters to be of clinical relevance, some recent reports have doubted the prognostic value of histology using modern treatment. Grading of the largest histologic category of Hodgkin disease, nodular sclerosis (NS), has been controversially discussed concerning clinical relevance. In this study, 965 cases of NS were reviewed to assess 9 histomorphologic parameters. The histologic results were correlated with laboratory and clinical findings and with overall survival and disease-free survival. Based on these results, a new grading of the NS category was established. The new grading, based on the 3 criteria eosinophilia, lymphocyte depletion, and atypia of the Hodgkin/Reed-Sternberg cells, was a significant indicator of prognosis in intermediate and advanced stages. Patients investigated in this study represent an outstanding collection because all of them were enrolled in the prospective multicenter clinical trial of the German Hodgkin Lymphoma Study Group. All of them had been staged uniformly according to the Ann Arbor system and had received stage-adapted modern treatment according to multimodality protocols. A subtle analysis of histology could represent a possible way to identify patients with a significantly better or worse prognosis. This new grading should help to avoid overtreatment to reduce severe therapy-related side effects such as acute toxicity and chronic sequelae such as cardiopulmonary complications and secondary neoplasias.