The clinical significance of anatomic substage was assessed in 130 patients with Hodgkin's disease in pathologic stage III-A: stage III-A includes involvement of spleen, or splenic, celiac, or portal nodes, or any combination of these; stage III-A includes involvement of para-aortic, iliac, or mesenteric nodes, with or without upper abdominal involvement. Median follow-up was 58 months. Both 5-year disease-free survival, 74% versus 46%, and 5-year survival, 94% versus 65%, were better (P < 0.001) in stage III-A than in stage III2-A. In stage III,-A, 5-year disease-free survival was better in patients receiving radiotherapy and chemotherapy than in patients receiving radiotherapy alone as initial treatment, 96% versus 63%, P < 0.003; however, 5-year survival rates in these treatment groups were similar, 100% versus 91%, P = 0.22. For stage III2-A, both 5-year disease-free survival, 76% versus 32%, P < 0.001, and 5-year survival, 84% versus 56%, P < 0.03, were superior with radiotherapy-chemotherapy. Consideration of anatomic substage may aid therapeutic planning for stage III Hodgkin's disease.