Background: The aim of this study was to assess the use of the baseline PSMA parotids uptake as a reference to determine eligibility for Lu-177 PSMA radioligand therapy (RLT) by using semi-quantitative and standardized visual criteria. Methods: We conducted a retrospective cohort study using a multicenter dataset 270 men with mCRPC treated with Lu-177 PSMA (Gafita A, Lancet Oncol 2021). For quantitative analysis, semi-automatic segmentation software (qPSMA) divided men into three groups according to the SUVmean ratio of whole-body-tumor to parotid glands: (high) > 1.5; (intermediate) 0.5 - 1.5; (low) < 0.5. For visual analysis, ten nuclear medicine physicians with (n = 5) and without (n = 5) clinical experience in Lu-177 PSMA RLT ( > 50 cases) read each baseline PSMA PET 3D maximum intensity projection (MIP) images, and classified the patients into three groups: (high) most ( > 80%) of the lesions show higher uptake than parotid glands; (intermediate) neither “low” nor “high”; (low) most ( > 80%) of the lesions show lower uptake than parotid glands. In case of inter-reader disagreement, a majority vote was used. Outcome measures included PSA-progression free-survival (PSA-PFS), overall survival (OS), and PSA decline of ≥50% (PSA50). Fisher’s exact test and Kaplan–Meier analysis with the log-rank test was performed for PSA50 and survival analysis, respectively. Results: 237 men were analyzed after excluding 33 men with more than half of the parotid glands out of the PET scan field-of-view. The number of the patients in the high, intermediate, and low groups were 106/237 (44.7%), 96 (40.5%), and 35 (14.8%) for visual criteria, and 56 (23.6%), 163 (68.8%), and 18 (7.6%) for quantitative analysis, respectively. The inter- and intra-readers reproducibility of the visual scoring showed substantial (Fleiss’ weighted Kappa: 0.68) and almost perfect (Cohen's weighted Kappa (mean): 0.83) agreement, respectively. The median PSA-PFS was 6.7, 3.8, and 1.9 months (p < 0.001); and 7.2, 4.0, and 1.9 months (p < 0.001) in the high, intermediate, and low expression groups by visual and quantitative criteria, respectively. The PSA50 was 63.2%, 33.3%, and 17.1% (p < 0.001), and 69.6%, 38.7%, and 16.7% (p < 0.001) in the high, intermediate, and low expression groups by visual and quantitative criteria, respectively. OS was longer in the high PSMA expression group than in the intermediate + low (i.e., non-high) group by visual (14.3 vs.11.0 months (p = 0.038)) and quantitative criteria (15.0 vs. 11.7 months (p = 0.013)). Conclusions: Tumor-to-parotid uptake using a simple visual or semi-quantitative measure is a valuable prognostic biomarker for response in men with mCRPC treated with Lu-177 PSMA RLT.