Background: PSMA-based imaging improves detection of metastatic disease for initial staging of men diagnosed with prostate cancer (PCa) with higher accuracy compared to conventional imaging. PSMA imaging is now being increasingly adopted for initial local and distant metastatic staging. We sought to determine the contribution of clinical and pathological factors associated with PSMA positive nodal or metastatic disease. Methods: We retrospectively identified 404 men diagnosed with PCa who underwent initial staging with Gallium-68 or F-18 piflufolastat (DCFPyL) PSMA PET/CT across our eleven-hospital system from July 2021-December 2022. Patient characteristics, including demographic, clinical, pathologic, and imaging variables were obtained. PSMA positivity representing a suspicious nodal or distant lesion was determined based on radiology reports, histopathology, and other imaging modalities, and equivocal or likely benign lesions were counted as negative. Patients with prior diagnosis (>6 months) of PCa (n=42) or incomplete clinical history (n=22) were excluded. Clinical variables were compared with Wilcoxon Rank Test, Chi square, and Fishers’ exact test as well as univariable and multivariable logistic regression. Number of risk factors for patients with unfavorable intermediate or very high risk disease was also examined. PSA was log transformed. Statistical significance was defined as p<0.05. Results: 103/340 patients (30.3%) had PSMA imaging findings concerning for nodal or distant metastatic disease. Patients with positive finding were less likely to be Black, and had higher PSA, biopsy Gleason Grade Group, and higher presumptive NCCN risk. Stratifying by pre-scan NCCN risk group, PSMA positivity was observed in no patients with favorable intermediate risk PCa (n=17), 9.8% (12/123) with unfavorable intermediate risk PCa, 29% (25/86) with high risk PCa, and 58% (66/114) with very high risk PCa. Stratifying by number of risk factors, there were significant differences in scan positivity comparing unfavorable intermediate risk disease with 1 vs ≥2 risk factors (4.2% vs 17%, p=0.03) and very high risk disease with 1 risk vs ≥2 risk factors (49% vs 72%, p=0.01). On multivariable analysis, NCCN classification stratified by risk factors was associated with PSMA positivity while Black race was inversely associated (OR 0.32, 95% CI 0.11, 0.82, p=0.03). Conclusions: Initial staging with PSMA PET/CT identified local regional or metastatic disease in 30% of PCa patients. A substantial proportion of unfavorable intermediate risk men were N1 or M1 based on PSMA positivity, particularly those with multiple unfavorable intermediate risk features. The clinical benefit for PSMA PET/CT in patients with favorable intermediate risk PCa is low. Limitations include retrospective design (including possible selection bias for patients with equivocal lesions on conventional imaging) and a limited number of black men in the cohort.