Background: Level one evidence shows that men with low-risk prostate cancer undergoing active surveillance (AS) with repeated PSA tests and systematic biopsies have low mortality. However, monitoring sometimes misses significant cancer progression and causes patient morbidity. The objective of this study is to evaluate a new proposed protocol for AS using the combination of the Stockholm3 test and MRI targeted biopsies in comparison to conventional follow-up using PSA and systematic biopsies. Methods: A prospective multicenter study with paired design was used to evaluate our proposed protocol (Stockholm3, MRI, targeted biopsies) compared with the conventional protocol according to Swedish National Guidelines (PSA, systematic biopsies) for follow-up of men on AS. The STHLM3 study was performed between 2012-2014. In the study 1 374 men were diagnosed with ISUP grade 1 disease. Out of these, 541 men currently on AS were invited to the STHLM3AS study. Eligible individuals had to be alive without any severe comorbidity, without contraindications for MRI and without a history of initiating prostate cancer treatment. The primary endpoint ISUP grade ≥2 cancer and the secondary endpoint number of performed biopsies will be evaluated using relative sensitivity (RS). At baseline a blood test for PSA and Stockholm3 test as well as a bi-parametric MRI was performed. For men with PIRADS ≥ 3 targeted and systematic biopsies were performed. For men with PIRADS < 3 only systematic biopsies were performed. The study is registered at ClinicalTrials.gov (NCTNCT03956108). Results: 301 men on AS have been included in the study. Since this is a trial in progress, no results will be presented. Conclusions: To our knowledge, this is the largest prospective multicenter study evaluating the performance of MRI for disease monitoring in an AS-cohort. Prediction models using biomarkers and MRI will likely both have an increasing role in the monitoring of AS patients in the future. We hypothesise that the sequential use of first Stockholm3 test followed by MRI will decrease the number of biopsies, while retaining the sensitivity to detect ISUP grade ≥2 cancer compared with using systematic biopsies in all men. Clinical trial information: NCTNCT03956108.