Background: We assessed whether interim positron emission tomography (iPET) had a prognostic value for diffuse large B-cell lymphoma (DLBCL) and whether PET-driven intensiﬁed therapy was needed. Methods: A prospective analysis of newly diagnosed stage III-IV DLBCL patients treated was conducted. The iPET scan was performed after 4 cycles of RCHOP (rituximab 375 mg/m2 d1; cyclophosphamide 750 mg/m2 d2; doxorubicin 50 mg/m2 d2; vincristine 1.4 mg/m2 [maximum 2 mg] d2; prednisone 100 mg orally daily d2-6) in all cases. Patients received 2 additional cycles when they achieved complete response. If they achieved partial response (PR), they received 4 additional cycles, and a final PET scan (fPET) was performed. If they had stable disease or progressive disease (PD), they were excluded from the study. The primary endpoint was 3-year progression-free survival (PFS), and secondary endpoints included 3-year overall survival (OS) and objective response rate (ORR). The trial is registered with ClinicalTrials.gov, number NCT 01804127. Results: From 2013 to 2015, a total of 55 patients were enrolled and 53 with both baseline and iPET scans were analyzed for prognostic value. Thirty-nine patients had iPET-negative (iPET-) and 14 patients had iPET-positive (iPET+) scans (11 had PR and 3 had PD). The ORR was 94.3%. With a median follow-up time of 36.4 months, 3-year PFS was 65.7% and 3-year OS was 79.9% for the entire cohort (n=53), and the median PFS and OS were not yet reached. iPET- patients had a higher 3-year PFS rate (78.1%) than iPET+ patients (34.3%) with a P value lower than 0.01. A trend for improved OS was also observed, with 3-year OS of 87.1% versus 62.3% (P=0.03). All 11 patients who had iPET PR received another 4 cycles of RCHOP, and 10 underwent fPET. Six patients had fPET-negative (fPET-) and 4 had fPET-positive (fPET+) scans. The 3-year PFS did not differ significantly between the iPET- and fPET- patients. In the univariate analysis, iPET- was the sole independent prognostic factor for PFS. Conclusions: PET/CT has a good prognostic value in patients with advanced-stage DLBCL. There was little significant benefit to intensifying chemotherapy if the iPET scan was positive.