Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas with poor outcomes on current therapy. We investigated whether response assessed with PET/CT combined with baseline total metabolic tumor volume (TMTV) could detect early relapse or refractory disease. Methods: From 7 European centers, 140 patients with nodal PTCL who underwent baseline PET/CT were selected. Forty-three had interim PET (iPET) performed after 2 cycles (iPET2), 95 had iPET performed after 3 or 4 cycles (iPET3/4), and 96 had end-of-treatment PET (eotPET). Baseline TMTV was computed with a 41% SUV _max threshold, and PET response was reported using the Deauville 5-point scale. Results: With a median of 43 mo of follow-up, the 2-y progression-free survival (PFS) and overall survival (OS) were 51% and 67%, respectively. iPET2-positive patients (Deauville score ≥ 4) had a significantly worse outcome than iPET2-negative patients (P < 0.0001, hazard ratio of 6.8 for PFS; P < 0.0001, hazard ratio of 6.6 for OS). The value of iPET3/4 was also confirmed for PFS (P < 0.0001) and OS (P < 0.0001). The 2-y PFS and OS for iPET3/4-positive (n = 28) and iPET3/4-negative (n = 67) patients were 16% and 32% versus 75% and 85%, respectively. The eotPET results also reflected patient outcome. A model combining TMTV and iPET3/4 stratified the population into distinct risk groups (TMTV ≤ 230 cm ³ and iPET3/4-negative [2-y PFS/OS, 79%/85%]; TMTV > 230 cm ³ and iPET3/4-negative [59%/84%]; TMTV ≤ 230 cm ³ and iPET3/4-positive [42%/50%]; TMTV > 230 cm ³ and iPET3/4-positive [0%/18%]). Conclusion: iPET response is predictive of outcome and allows early detection of high-risk PTCL patients. Combining iPET with TMTV improves risk stratification in individual patients.