Abstract Objectives To develop an automatic method for identification and segmentation of clinically significant prostate cancer in low-risk patients and to evaluate the performance in a routine clinical setting. Methods A consecutive cohort (n = 292) from a prospective database of low-risk patients eligible for the active surveillance was selected. A 3-T multi-parametric MRI at 3 months after inclusion was performed. Histopathology from biopsies was used as reference standard. MRI positivity was defined as PI-RADS score ≥ 3, histopathology positivity was defined as ISUP grade ≥ 2. The selected cohort contained four patient groups: (1) MRI-positive targeted biopsy-positive (n = 116), (2) MRI-negative systematic biopsy-negative (n = 55), (3) MRI-positive targeted biopsy-negative (n = 113), (4) MRI-negative systematic biopsy-positive (n = 8). Group 1 was further divided into three sets and a 3D convolutional neural network was trained using different combinations of these sets. Two MRI sequences (T2w, b = 800 DWI) and the ADC map were used as separate input channels for the model. After training, the model was evaluated on the remaining group 1 patients together with the patients of groups 2 and 3 to identify and segment clinically significant prostate cancer. Results The average sensitivity achieved was 82–92% at an average specificity of 43–76% with an area under the curve (AUC) of 0.65 to 0.89 for different lesion volumes ranging from > 0.03 to > 0.5 cc. Conclusions The proposed deep learning computer-aided method yields promising results in identification and segmentation of clinically significant prostate cancer and in confirming low-risk cancer (ISUP grade ≤ 1) in patients on active surveillance. Key Points • Clinically significant prostate cancer identification and segmentation on multi-parametric MRI is feasible in low-risk patients using a deep neural network. • The deep neural network for significant prostate cancer localization performs better for lesions with larger volumes sizes (> 0.5 cc) as compared to small lesions (> 0.03 cc). • For the evaluation of automatic prostate cancer segmentation methods in the active surveillance cohort, the large discordance group (MRI positive, targeted biopsy negative) should be included.