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Less than half of all patients with aggressive non-Hodgkin's lymphoma (NHL) are cured with standard chemotherapy. Therefore, it is important to distinguish between responders to standard treatment and non-responders who may benefit from an early change to a more effective therapy. This study was intended to assess the value of a midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) scan to predict clinical outcome in patients with aggressive NHL.Seventy newly diagnosed patients with aggressive NHL, who were treated with doxorubicin-containing chemotherapy, underwent a [18F]FDG-PET scan at midtreatment. Presence or absence of abnormal [18F]FDG uptake was related to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier survival analysis. Multivariate analysis was performed to evaluate the effect of the International Prognostic Index (IPI) and early [18F]FDG-PET findings on PFS and OS.At midtreatment, 33 patients showed persistent abnormal [18F]FDG uptake and none of these patients achieved a durable complete remission (CR), whereas 37 patients showed a negative scan; 31/37 remained in CR, with a median follow-up of 1107 days. Only 6/37 patients either achieved a partial response or relapsed. Comparison between groups indicated a statistically significant association between [18F]FDG-PET findings and PFS (P <1 × 10−5) and OS (P <1 × 10−5). In multivariate analysis, [18F]FDG-PET at midtreatment was a stronger prognostic factor for PFS (P <1 × 10−7) and OS (P <9 × 10−6) than the IPI (P <0.11 and P <0.03, respectively).Early restaging [18F]FDG-PET may be used to tailor induction chemotherapy in patients with aggressive NHL.