As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial FDG-PET at baseline, after two cycles of chemotherapy (i-PET), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by two imaging experts, using the visual 5-point scale (5-PS), and by calculating percent change in FDG uptake (ΔSUV). Visual scores of 1-3 and ΔSUV ≥ 66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (HR=0.99, 95% CI: 0.97-1.00, p=0.02) and overall survival (OS) (HR=0.98, 95% CI: 0.97-0.99, p=0.03). ΔSUV ≥ 66% was predictive of OS (HR=0.31, 95% CI: 0.11-0.85, p=0.02) but not PFS (HR=0.47, 95% CI: 0.19-1.13, p=0.09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This study was registered at clinicaltrials.gov as NCT00118209.