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To assess the performance of multiparametric (mp) MRI in identification of intraprostatic tumor deposits in patients previously treated with local radiation therapy (RT) using a systematic and targeted MR-gided transperineal prostate biopsy technique. Thirty patients with a rising PSA and negative metastatic work up after prior external beam RT, brachytherapy, or combined external beam RT and brachytherapy for localized prostate cancer underwent a combined systematic and targeted MRI-guided prostate biopsy using a transperineal approach. For each patient, a pre-biopsy mpMRI scan was obtained and imported into a prostate biopsy planning system. Transverse T2-weighted images were then reoriented from the supine to dorsal lithotomy position. Dividing the prostate into an apical and base section, a systematic array of transperineal biopsies spaced approximately 10mm apart was planned with additional biopsies targeting any mpMRI-identified PI-RADS 3, 4, or 5 lesion. Biopsy procedures were carried out under general anesthesia in the dorsal lithotomy position using a transrectal ultrasound with stepper-stabilizer and template grid. Matching of the planning mpMRI images to live ultrasound images was achieved using the template grid as a reference. All patients successfully underwent biopsy without post-procedure urinary obstruction or infection. The median prostate volume was 36cc (range 12-90, IQR 24-51). The median PSA prior to biopsy was 4.7 ng/mL (range 1.9-24.6, IQR 3.0-7.3). The median number of biopsy specimens obtained per patient was 21 (range 13-34, IQR 17-24). A total of 32 PI-RADS lesions were identified in 30 patients. Overall, the positive predictive value (PPV) of any PI-RADS 3-5 lesion for prostate cancer (based on pathologic confirmation) was 84% (27/32). The individual PPV of PI-RADS 3, 4 and 5 lesions were 40% (2/5), 89% (17/19), and 100% (8/8), respectively. Forty-three percent (13/30) of patients harbored mpMRI-unidentified prostate cancer. Thirty percent (9/30) of patients harbored mpMRI-unidentified GS≥7 disease. Using prostate mpMRI to identify intraprostatic tumor deposits after local radiation therapy results in a high PPV, particularly for PI-RADS 4 and 5 lesions. However, given the high rate of mpMRI-unidentified prostate cancer, the addition of systematic transperineal prostate biopsy information appears necessary to most accurately identify all intraprostatic tumor deposits. These data would suggest that a combination of systematic and mpMRI targeted biopsies are necessary to optimally perform focal salvage therapy in the setting of local recurrence after radiation therapy. [ABSTRACT FROM AUTHOR]