Background: Peptide receptor radionuclide therapy (PRRT) is an effective therapy for metastatic/inoperable neuroendocrine tumors (NETs). Tools to predict and monitor the efficacy of therapy are important adjuncts in the radio-oncology armamentarium. Standard blood biomarkers are not effective by new molecular based assays such as the PRRT Predictive Quotient (PPQ) and NETest are effective as real-time predictors and monitors of therapy. We aimed to prospectively evaluate whether: 1) the NETest functioned as a surrogate biomarker for image-based per RECIST evaluation of PRRT efficacy; 2) there was a correlation between changes in NETest levels during therapy, PPQ prediction and treatment efficacy. Methods: Three independent ¹⁷⁷Lu-PRRT-treated GEP-NET and BPNEN cohorts (Rotterdam, Netherlands: n= 41; Bad-Berka, Germany: n= 44; Meldola, Italy: n= 72). Treatment response: RECIST1.1 [Responder (stable, partial/complete response) vs Non-Responder]. Blood sampling: pre-PRRT, prior to each cycle and 6 months (median) after completion of all cycles. PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable<40; progressive > 40). CgA (ELISA) as comparator. Samples deidentified, measurement and analyses blinded. Kaplan-Meier survival and Mann-Whitney analyses. Results: 122 of 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p< 0.0001) decreased in RECIST-“responders” (-47±3%); in “non-responders” it elevated (+79±19%, p< 0.0005). NETest monitoring accuracy 98% (119/122). Follow-up levels > 40 (progressive) vs stable (<40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04, 95%CI: 0.02-0.07). PPQ response prediction was accurate in 118 (97%); 99% accurate positive and 93% accurate negative prediction. NETest significantly (p< 0.0001) decreased in PPQ-predicted responders (-46±3%) and remained increased in PPQ-predicted non-responders (+75±19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06, 95%CI: 0.03-0.12). In comparison, the standard biomarker, CgA, failed to predict or correlate with response to PRRT (p= NS). Conclusions: NETest accurately (98%) monitors PRRT response and is an effective surrogate marker for radiological response (image concordance 98%). A NETest decrease identified responders (99%) and correlated ( > 97%) with the pretreatment PPQ response predictor.