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In this study, we investigated the prognostic role of interim fluorine-18-fluorodeoxyglucose PET/computed tomography (I-PET/CT) and BCL2 in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab-containing chemotherapy.A total of 106 patients with newly diagnosed DLBCL underwent PET/CT scans at baseline and a subsequent I-PET/CT after the fourth cycle of chemotherapy. I-PET/CT was analyzed using the Deauville five-point score. The prognostic significance of I-PET/CT and BCL2 was evaluated by predicting progression-free survival (PFS) and overall survival (OS).With a median follow-up of 25 months, the 2-year PFS and OS were 78 and 95% in the I-PET/CT-negative group and 33 and 57% in the I-PET/CT-positive group (P<0.001). Patients with BCL2 positivity showed a shorter PFS than the BCL2-negative patients (P=0.002), but not in OS (P=0.068). In multivariate analysis, I-PET/CT and BCL2 were independent variables in assessing the outcome of PFS. I-PET/CT was also an independent factor for OS. Irrespective of the results of BCL2, patients with I-PET/CT positivity had a significant inferior outcome than the I-PET/CT-negative patients. In the I-PET/CT-negative group, patients with BCL2 positivity had a significantly shorter PFS than the BCL2-negative patients (P=0.005).I-PET/CT and BCL2 were two significant independent indicators of outcome for patients with DLBCL in the rituximab era. I-PET/CT was much better than BCL2 for patient stratification. BCL2 showed its supplementary role for further patient stratification when I-PET/CT was negative.