OBJECTIVE : To investigate which clinical and radiological characteristics can predict clinically significant prostate cancer (csPCa) in PI-RADS 3 lesions. To investigate which clinical and radiological characteristics influence the clinician to biopsy a PI-RADS 3 lesion. METHODS : mpMRI PI-RADS 3 lesions scored by 1 out of 3 highly specialized radiologists in a single high-volume center during the period March 2015 to August 2017 were investigated. This score was based on T2 weighted and diffusion weighted imaging (DWI) sequences. Clinical characteristics of all patients with PI-RADS 3 lesions were collected from medical records. Radiological characteristics were collected from radiology reports. Some radiological characteristics such as apparent diffusion coefficient (ADC) in a region of interest at the tumor site and ADC at a site contralateral to the tumor site were calculated on DWI sequences. Cox regression analysis was performed to identify which characteristics could predict csPCa in PI-RADS 3 lesions and which characteristics could influence the behavior of a clinician whether or not to biopsy a PI-RADS 3 lesion. RESULTS : csPCa could be detected in 31 out of 131 patients with PI-RADS 3 lesions (22.9%). A lower median prostate volume (p = 0.015) and a lower ratio of ADC of the tumor on ADC of the contralateral prostate (ADCT/ADCCLP) (p < 0.001) significantly predisposed for csPCa in multivariate logistic regression. For peripheral zone lesions, a diagnostic model with biopsy of only those PI-RADS 3 lesions with a prostate volume <44 cc and a ratio of ADCT/ADCCLP < 70% showed a sensitivity for detection of csPCa of 59% with a specificity of 88%. (area under the curve 0.780) A suspicious rectal examination (p = 0.011) and the mentioning of prostatitis on the MRI report (p = 0.020) influenced clinicians to biopsy a PI-RADS 3 lesion positively and negatively respectively. For transition zone lesions, previous negative biopsies (p = 0.044) predisposed for csPCa. CONCLUSIONS : Prostate volume and the ratio of ADC tumor on ADC of the contralateral prostate have the potential to predict csPCa in PI-RADS 3 lesions with a sensitivity of 59% and specificity of 88%. A suspicious rectal examination and the mentioning of prostatitis on the MRI report influenced the decision of clinicians to biopsy a PI-RADS 3 lesion.