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Objective To retrospectively assess the rate of high-grade primary Gleason upgrading ( HGPGU) to primary Gleason pattern 4 or 5 in a contemporary cohort of patients with D'Amico low-risk prostate cancer including those who fulfilled Prostate Cancer Research International Active Surveillance ( PRIAS) criteria, and to develop a tool for HGPGU prediction. HGPGU is a contraindication in most active surveillance ( AS) and focal therapy protocols. Patients and Methods In all, 10 616 patients with localised prostate cancer were treated at a high-volume European tertiary care centre from 2010 to 2015 with radical prostatectomy. Analyses were restricted to 1 819 patients with D'Amico low-risk prostate cancer (17.1%) with prostate-specific antigen ( PSA) levels of <10.0 ng/mL, cT1c- cT2a and Gleason score ≤6, and were repeated within 772 of the men (7.3%) who fulfilled the PRIAS criteria for AS ( PSA level of ≤10 ng/mL, T1c-T2, Gleason score ≤6, PSA density ( PSAD) of <0.2 ng/mL2, ≤2 positive cores). Uni- and multivariable logistic regression models were fitted, testing predictors of HGPGU. The final logistic regression model was based on the most informative variables. Results There was HGPGU in 88 (4.8%) patients with D'Amico low-risk prostate cancer and in 32 (4.1%) of the subgroup who were PRIAS eligible. Multivariable analysis predicting HGPGU for the patients with D'Amico low-risk yielded three independent predictors: age, PSAD, and clinical tumour stage ( P = 0.008, P = 0.005 and P = 0.021, respectively). Within the same patients, the model using all vs the most informative variables resulted in area under the curves ( AUCs) of 69.2% and 68.3%, respectively. Multivariable analysis of those who were PRIAS eligible, yielded age and number of positive cores as independent predictors of HGPGU ( P = 0.002 and P = 0.049, respectively; AUC 64.9%). Conclusions The low accuracy (invariably <70%) for HGPGU prediction in both patients with D'Amico low-risk prostate cancer and PRIAS eligibility indicates that these variables have poor predictive ability in contemporary patients. Despite HGPGU being a rare phenomenon, it may have life threatening implications and consequently alternatives such as biomarkers, genetic markers, or imaging modalities at re-biopsy are needed. [ABSTRACT FROM AUTHOR]