The aim of the study was to assess the outcome of patients with metastatic castration-resistant prostate cancer treated with Lu-prostate-specific membrane antigen (PSMA) who would have been a screen failure (SF) in the VISION trial based on PSMA PET/CT criteria. We conducted a retrospective multicenter cohort study on 301 patients with metastatic castration-resistant prostate cancer treated with Lu-PSMA. The patients were classified into eligible (VISION-PET-E) and SF (VISION-PET-SF) groups on the basis of the baseline PSMA PET/CT results. Prostate-specific antigen (PSA) response rates, PSA progression-free survival, and overall survival were compared. Of 301 patients, 272 (90.4%) and 29 (9.6%) were VISION-PET-E and VISION-PET-SF, respectively. The VISION-PET-SF patients had a worse rate of ≥50% PSA decline (21% vs. 50%,  = 0.005) and PSA progression-free survival (2.1 vs. 4.1 mo,  = 0.023) and tended to have a shorter overall survival (9.6 vs. 14.2 mo.  = 0.16) than the VISION-PET-E patients. The VISION-PET-SF patients had worse outcomes than the VISION-PET-E patients. Our cohort did not include preexcluded patients (10%-15%) by local site assessments. Thus, 20%-25% of the patients may be SFs in unselected populations. Refinements in patient selection for Lu-PSMA are needed to optimize outcomes.