The utility of circulating tumor DNA (ctDNA) for mutational genotyping, pretreatment prognostication, and assessment of molecular response is well established in patients with aggressive large B-cell lymphoma (LBCL). Here, we have applied targeted panel and duplex sequencing of plasma ctDNA to study copy number aberrations (CNAs) along with mutational landscapes in 123 uniformly treated patients with high-risk LBCL. We find a robust correlation between targeted and whole-genome sequenced CNA landscapes (R = 0.81) and identify CNAs in the ctDNA in 76% of the patients above the limit of detection. We describe the most frequently affected genomic regions, their interactions with diagnostic and genetic subtypes, and associations with overall and progression-free survival. Specifically, we show how ctDNA profiling of TP53 loss outperforms fluorescence in situ hybridization (FISH)-based TP53/17p analysis in risk assessment, independent of clinical risk factors and ctDNA concentration. We validate key findings of prognostic tumor fraction and TP53 loss in an independent LBCL cohort. Furthermore, we detect dynamic shifts between the fractions of lymphoma clones by assessing CNAs and mutations in the ctDNA at disease progression. These findings demonstrate the potential of minimally invasive, targeted CNA analysis in resolving the molecular heterogeneity of LBCLs.