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Revised response criteria for aggressive lymphomas have been proposed (Cheson, J Clin Oncol, 2007) stressing the role of 18fluorodeoxyglucose–positron emission tomography (PET) in posttreatment evaluation. The value of PET after four cycles compared with the International Workshop Criteria (IWC) remains to be established.In all, 103 patients with untreated diffuse large B-cell lymphoma were prospectively enrolled to evaluate the prognostic impact of PET after two and four cycles.Median age was 53 years (19–79), 68% male. The International Prognostic Index was low=22%, low-intermediate=19%, intermediate-high=33% and high risk=26%. Treatment consisted of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (30%) or dose-intensified CHOP (70%), with rituximab (49%) or without (51%). Ninety-nine patients were evaluated by PET and IWC at four cycles: 77 (78%) had a negative PET, while 22 (22%) remained positive. The 5-year event-free survival (EFS) was 36% for patients with a positive PET versus 80% with a negative examination, whatever the response [complete response (CR) versus partial response (PR)] according to IWC (P < 0.0001). Positive PET patients had a 5-year EFS of 58% if in CR/CR unconfirmed by IWC and 0% if not (P < 0.0001). The same observations could be made in patients treated with and without rituximab.The integration of PET in treatment evaluation offers a powerful tool to predict outcome.