Our objective was to develop version 1.0 of a novel framework for response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by prostate-specific antigen (PSA) measurements and by RECIP 1.0 (PSA + RECIP). This was an international multicenter, retrospective study. One hundred twenty-four men with metastatic castration-specific prostate cancer (mCRPC) who underwent Lu-PSMA therapy and received PSMA PET/CT at baseline and at an interim time point of 12 wk were included. Pairs of baseline interim PET/CT scans were interpreted by consensus among 3 masked readers for appearance of new lesions. Tumor lesions were segmented, and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which included classifications of complete response (RECIP-CR: absence of any PSMA-ligand uptake on interim PET/CT), partial response (RECIP-PR: decline ≥ 30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥ 20% in PSMA-VOL and appearance of new lesions), and stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 wk by Prostate Cancer Working Group Criteria 3 were recorded. PSA + RECIP results were defined as response (PSA decline ≥ 50% or RECIP-PR/CR) or progression (PSA increase ≥ 25% or RECIP-PD). The study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). The secondary outcome measure was the prognostic accuracy (C-index) of PSA + RECIP versus PSA responses. Patients with RECIP-PD ( = 39; 8.3 mo) had a shorter OS than patients with stable disease (RECIP-SD) ( = 47; 13.1 mo; < 0.001) or RECIP-PR ( = 38; 21.7 mo; < 0.001). In identifying responders and progressors, PSA + RECIP had C-indices superior to those of PSA only: 0.65 versus 0.62 ( = 0.028) and 0.66 versus 0.63 ( = 0.044), respectively. PSMA PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor early efficacy of Lu-PSMA in men with mCRPC. PSA + RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.