This study analyzed the genetics of classic Hodgkin lymphoma (cHL) by using circulating tumor DNA (ctDNA). Two genetic subtypes were identified, differing in genetic instability mechanisms: one subtype (64% of cases) showed a higher mutation load and a higher fraction of mutations associated with activation-induced cytidine deaminase and microsatellite instability signatures, whereas the other subtype (36% of cases) exhibited chromosomal instability with more somatic copy number alterations. Whole-genome duplication was more common in cHL compared with other B-cell tumors and emerged as a prognostic biomarker for patients undergoing Adriamycin (doxorubicin)-bleomycin-vinblastine-dacarbazine–based therapy. Noncoding regulatory mutations, similar to those in diffuse large B-cell lymphoma, were highly prevalent in 86% of cHL. A recurrent somatic expression quantitative trait locus (seQTL) involving the BCL6 gene was found in 30% of cases. The seQTL of BCL6 aligned with accessible chromatin and increased H3K27 acetylation in cHL, disrupted PRDM1 binding, and co-occurred with BCL6 expression in cHL cells. Weak to strong expression of BCL6 was observed in 68% of cases, and BCL6 expression associated with gene repression similarly in cHL and germinal center B cells. After BCL6 degradation, the core set of genes directly bound and regulated by BCL6 was derepressed in cHL, and proliferation was impaired. The number and clonality of neoantigens was associated with tumor microenvironment type and response to checkpoint blockade. Finally, ctDNA analysis was suggested as a tool to distinguish ambiguous positron emission tomography/computed tomography–positive lesions after treatment.