PURPOSE Large B-cell lymphomas (LBCLs) are curable, but patients with residual disease after therapy invariably experience progression. Ultrasensitive methods to detect circulating tumor DNA (ctDNA) as minimal residual disease (MRD) may improve the determination of remission. METHODS We integrated data from five prospective studies of frontline anthracycline-based chemotherapy in patients with LBCL. Tumor-specific phased variants were identified from pretreatment samples and monitored at landmark time points. Serial plasma specimens were blindly analyzed for detectable ctDNA as MRD. MRD status was compared with conventional response criteria for prognosis of progression-free survival (PFS). RESULTS We studied ctDNA-MRD in 137 patients by monitoring 409 plasma specimens over time. Detectable ctDNA rates decreased during therapy with 55% and 78% of patients achieving undetectable ctDNA after two cycles and at the end of therapy, respectively. After a median follow-up of 37 months, the 2-year PFS for patients with detectable versus undetectable ctDNA after two cycles was 67% versus 96% ( P = .0025; hazard ratio [HR], 6.9) and after therapy was 29% versus 97% ( P < .0001; HR, 28.7), respectively. Ninety-two (94%) patients with undetectable ctDNA at the end of therapy remained alive without progression, while 19 (68%) patients with detectable ctDNA progressed or died. MRD status at the end of therapy had greater prognostic utility than conventional lymphoma response criteria using positron emission tomography (PET) scans (HR, 3.6 for positive PET and 28.3 for detectable ctDNA). CONCLUSION Ultrasensitive ctDNA detection after frontline LBCL therapy is more prognostic than conventional radiographic response criteria. A refined definition of remission with ctDNA-MRD may improve clinical and psychological outcomes for patients with LBCL.