Indeterminate bone lesions (IBLs) on prostate-specific membrane antigen (PSMA) PET/CT are common. This study aimed to define variables that predict whether such lesions are likely malignant or benign using features on PSMA PET/CT. F-DCFPyL PET/CT imaging was performed on 243 consecutive patients with high-risk primary or biochemically recurrent prostate cancer. IBLs identified on PSMA PET/CT could not definitively be interpreted as benign or malignant. Medical records of patients with IBLs were reviewed to determine the ultimate status of each lesion. IBLs were deemed malignant or benign on the basis of evidence of progression or stability at follow-up, respectively, or by biopsy results; IBLs were deemed equivocal when insufficient or unclear evidence existed. Post hoc patient, lesion, and scan variables accounting for clustered data were evaluated using Wilcoxon rank-sum and χ tests to determine features that favored benign or malignant interpretation. Overall, 98 IBLs within 267 bone lesions (36.7%) were identified in 48 of 243 patients (19.8%). Thirty-seven of 98 IBLs were deemed benign, and 42 were deemed malignant, of which 8 had histologic verification; 19 remained equivocal. Location and SUV categorical variables were predictive of IBL interpretation ( = 0.0201 and = 0.0230, respectively). For IBLs with new interpretations, 34 of 37 (91.9%) considered benign showed an SUV of less than 5 or exhibited focal uptake without coexisting bone metastases; 37 of 42 (88.1%) deemed malignant demonstrated an SUV of at least 5 or were present with coexisting bone metastases. Logistic regression predicted IBLs with a high SUV (univariable: odds ratio [OR], 9.29 [ = 0.0016]; multivariable: OR, 13.87 [ = 0.0089]) or present with other bone metastases (univariable: OR, 9.87 [ = 0.0112]; multivariable: OR, 11.35 [ = 0.003]) to be malignant. IBLs on PSMA PET/CT are concerning; however, characterizing their location, SUV, and additional scan findings can aid interpretation. IBLs displaying an SUV of at least 5 or present with other bone metastases favor malignancy. IBLs without accompanying bone metastases that exhibit an SUV of less than 5 and are observed only in atypical locations favor benign processes. These guidelines may assist in the interpretation of IBLs on PSMA PET/CT.