Abstract In the phase 3 ECHELON-2 trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV-CHP) significantly improved progression-free survival (PFS) and overall survival (OS) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30+ peripheral T-cell lymphoma, benefits that were maintained at 5 years. Interim positron emission tomography (PET) scan can be used to assess prognosis and risk-stratify patients. The prognostic value of interim PET was assessed in this post hoc exploratory analysis from ECHELON-2, evaluating interim 18F-fluorodeoxyglucose PET scans after cycle 4 (PET4) and end-of-treatment–based response, and correlated with PFS per investigator and OS. PET4 response was determined by Deauville score (scores of 1-3 were considered negative [PET4-negative] and 4-5 positive [PET4-positive]) by independent review. Overall, 452 patients were randomized 1:1 to the BV-CHP (n = 226) and CHOP (n = 226) arms. Of these, 32 in the BV-CHP arm and 41 in the CHOP arm were not evaluable for PET4. In both arms, PET4-negative status was associated with improved PFS (BV-CHP: HR, 0.36; 95% CI, 0.19-0.66; CHOP: HR, 0.26; 95% CI, 0.17-0.41) and OS (BV-CHP: HR, 0.38; 95% CI, 0.18-0.78; CHOP: HR, 0.24; 95% CI, 0.14-0.41) compared with PET4-positive status. Among patients with systemic anaplastic large cell lymphoma, PET4-negative patients had improved PFS (BV-CHP: HR, 0.28; 95% CI, 0.14-0.60; CHOP: HR, 0.31; 95% CI, 0.17-0.56) and OS (BV-CHP: HR, 0.38; 95% CI, 0.16-0.94; CHOP: HR, 0.25; 95% CI, 0.12-0.55) compared with PET4-positive patients. In this exploratory analysis, PET4-negative status by Deauville score was associated with improved long-term PFS and OS in both the BV-CHP and CHOP arms. This trial was registered at www.ClinicalTrials.gov as #NCT01777152.