A 17-year-old boy presented with intermittent cough, fatigue, and fever. Computed tomography showed a mediastinal mass and hypodense splenic lesions. Biopsy of the mediastinal mass revealed numerous follicles with atrophic germinal centers and “onion skin”-like expanded mantles penetrated by hyalinized vessels, morphologically consistent with hyaline vascular Castleman disease (CD) (panel A, hematoxylin and eosin [H&E] stain, original magnification ×100), and scattered interfollicular large atypical cells resembling Reed-Sternberg cells (panel B, H&E stain, original magnification ×400), which stained weakly positive for PAX-5 (panel C, original magnification ×400) and strongly positive for CD30 (panel D, original magnification ×400), consistent with classical Hodgkin lymphoma (cHL). The lymphoma cells were negative for CD20 and positive for CD15 (data not shown). Epstein-Barr virus and human herpesvirus 8 (HHV-8) were negative. Serum interleukin-6 was markedly elevated at 299 pg/mL (normally <5 pg/mL). The patient was diagnosed with stage IIIB cHL with features of CD, received standard therapy for cHL, and achieved complete remission.Association of interfollicular cHL and HHV-8–negative CD is rare but has been described. Recognition of this rare morphologic combination will promote correct diagnosis and proper clinical management. An adequate amount of tissue should be obtained to avoid missing the diagnosis of cHL, as small-needle core biopsy specimens may show only the pathologic changes of CD.