Background: PSMA-targeted radioligand therapy can improve the outcome of patients with advanced mCRPC. However, patients do not respond uniformly and a PSA decline of ≥50% (PSA50) was achieved only in 46% of the patients in the VISION trial. We hypothesized that using the parotid glands instead of the liver as the reference organ enables more selective stratification. The aim of this study was to test PSMA PET tumor-to-Salivary Glands ratio (PSG score) to predict outcomes after Lu-177 PSMA. Methods: This was an international multicenter retrospective study using the established dataset consisting of 270 men with mCRPC treated with Lu-177 PSMA (Gafita A, Lancet Oncol 2021). First, we assessed baseline PSMA PET quantitatively (qPSG score) to calculate the tumor-to-salivary gland ratio (qPSG = SUVmean whole-body-tumor / SUVmean parotid glands) using a semi-automatic segmentation software (qPSMA). Patients were divided into three groups: high (qPSG > 1.5), intermediate (qPSG = 0.5 - 1.5), and low (qPSG < 0.5). Second, we assessed the reproducibility and the predictive value of the PSG score visually (vPSG score) graded by ten nuclear medicine physicians. Each reader read the baseline PSMA PET 3D maximum intensity projection (MIP) images, and classified the patients into three groups: (high) most of the lesions (> 80%) show higher uptake than parotid glands; (intermediate) neither “low” nor “high”; (low) most of the lesions (> 80%) show lower uptake than parotid glands. In case of disagreement, a majority vote was used. Outcome measures were PSA-progression free-survival (PSA-PFS), overall survival (OS), and PSA50. Results: 237 men were analyzed after excluding 33 men whose parotid glands were out of the scan range. The number of the patients in the high, intermediate, and low groups were 56/237 (23.6%), 163 (68.8%), and 18 (7.6%) for qPSG score, and 106/237 (44.7%), 96 (40.5%), and 35 (14.8%) for vPSG score, respectively. The inter- and intra-readers reproducibility of the vPSG score showed substantial (Fleiss’ weighted Kappa: 0.68) and almost perfect (Cohen's weighted Kappa (mean): 0.83) agreement, respectively. The median PSA-PFS of high, intermediate, and low groups were 7.2, 4.0, and 1.9 months (p < 0.001) for qPSG score and 6.7, 3.8, and 1.9 months (p < 0.001) for vPSG score, respectively. Higher PSA50 rate was observed in the high group followed by the intermediate and low groups (high vs intermediate vs low: [qPSG] 69.6% vs 38.7% vs 16.7%; [vPSG] 63.2% vs 33.3% vs 16.1%). The median OS was longer in the high group than in the intermediate + low (i.e., non-high) group by qPSG (15.0 vs. 11.7 months (p = 0.013)) and vPSG score (14.3 vs.11.0 months (p = 0.038)). Conclusions: The PSG score is a valuable predictive biomarker for response to Lu-177 PSMA. The vPSG score yielded substantial reproducibility and comparable predictive value to the qPSG score.