The prognosis value of interim positron emission tomography (PET) remains controversial in diffuse large B-cell lymphoma (DLBCL) patients because of the absence of consensus on criteria able to early identify good and bad responders to treatment. Visual interpretation using the International Harmonization Project (IHP) criteria, primarily established for end of treatment evaluation, was related to a low positive predictive value of treatment failure. The 5-point scale (5PS) that refers the residual uptake to the liver as background tissue was shown to slightly reduce false-positive interim PET interpretations compared to IHP criteria. Semiquantification of fluorodeoxyglucose (FDG) uptake using standardized uptake value (SUV) and assessment of reduction of maximum SUV (SUVmax) between baseline and interim PET drastically improves both the interpretation accuracy and the interobserver reproducibility, and better predicts patient outcome than visual analysis. This latter approach is feasible in a multicenter setting and allows clinicians to design a risk-adapted therapeutic strategy based on early PET response assessment.