Early identification of patients with diffuse large B-cell lymphoma (DLBCL) who are likely to experience disease recurrence or refractory disease after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) would be useful for improving risk-adapted treatment strategies. We aimed to assess the prognostic value of F-FDG PET/CT parameters at baseline, interim, and end of treatment (EOT). We analyzed the prognostic impact of F-FDG PET/CT in 166 patients with DLBCL treated with a risk-adapted immunochemotherapy regimen. Scans were obtained at baseline, after 4 cycles of R-CHOP or 3 cycles of RR-CHOP (double dose of R) and 1 cycle of CHOP alone (interim) and 6 wk after completing therapy (EOT). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier and the impact of clinical/PET factors assessed with Cox models. We also assessed the predictive ability of the recently proposed International Metabolic Prognostic Index (IMPI). The median follow-up was 7.9 y. International Prognostic Index (IPI), baseline metabolic tumor volume (MTV), and change in maximum SUV (ΔSUV) at interim scans were statistically significant predictors for OS. Baseline MTV, interim ΔSUV, and EOT Deauville score were statistically significant predictors of PFS. Combining interim PET parameters demonstrated that patients with Deauville 4-5 and positive ΔSUV ≤ 70% at restaging (∼10% of the cohort) had extremely poor prognosis. The IMPI had limited discrimination and slightly overestimated the event rate in our cohort. Baseline MTV and interim ΔSUV predicted both PFS and OS with this sequential immunochemotherapy program. Combining interim Deauville score with interim ΔSUV may identify an extremely high-risk DLBCL population.