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To assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-L-cysteine) (18F-DCFBC), a prostate-specific membrane antigen–targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology.This Health Insurance Portability and Accountability Act of 1996–compliant, prospective, institutional review board–approved study included 13 evaluable patients with localized prostate cancer (median age, 62.8 years [range, 51–74 years]; median prostate-specific antigen, 37.5 ng/dL [range, 3.26–216 ng/dL]). Patients underwent mpMRI and 18F-DCFBC PET/CT within a 3 months' window. Lesions seen on mpMRI were biopsied under transrectal ultrasound/MRI fusion–guided biopsy, or a radical prostatectomy was performed. 18F-DCFBC PET/CT and mpMRI were evaluated blinded and separately for tumor detection on a lesion basis. For PET image analysis, MRI and 18F-DCFBC PET images were fused by using software registration; imaging findings were correlated with histology, and uptake of 18F-DCFBC in tumors was compared with uptake in benign prostatic hyperplasia nodules and normal peripheral zone tissue using the 80% threshold SUVmax.A total of 25 tumor foci (mean size, 1.8 cm; median size, 1.5 cm; range, 0.6–4.7 cm) were histopathologically identified in 13 patients. Sensitivity rates of 18F-DCFBC PET/CT and mpMRI were 36% and 96%, respectively, for all tumors. For index lesions, the largest tumor with highest Gleason score, sensitivity rates of 18F-DCFBC PET/CT and mpMRI were 61.5% and 92%, respectively. The average SUVmax for primary prostate cancer was higher (5.8 ± 4.4) than that of benign prostatic hyperplasia nodules (2.1 ± 0.3) or that of normal prostate tissue (2.1 ± 0.4) at 1 hour postinjection (P = 0.0033).The majority of index prostate cancers are detected with 18F-DCFBC PET/CT, and this may be a prognostic indicator based on uptake and staging. However, for detecting prostate cancer with high sensitivity, it is important to combine prostate-specific membrane antigen PET/CT with mpMRI.