BACKGROUND:Active surveillance (AS) has become the recommended management strategy for men with low-risk prostate cancer. However, there is considerable uncertainty about the optimal follow-up schedule in terms of the tests to perform and their frequency. OBJECTIVE:To assess the costs and benefits of different AS follow-up strategies compared to watchful waiting (WW) or immediate treatment. DESIGN, SETTING, AND PARTICIPANTS:A state-transition Markov model was developed to simulate the natural history (ie, no testing or intervention) of prostate cancer for a hypothetical cohort of 50-yr-old men newly diagnosed with low-risk prostate cancer. Following diagnosis, men were hypothetically managed with immediate treatment, watchful waiting, or one of several AS strategies. AS follow-up was performed either with transrectal ultrasound-guided biopsy or magnetic resonance imaging (MRI) which was scheduled annually, biennially, every 3yrs, according to the PRIAS protocol (yrs 1, 4, 7, and 10, and then every 5yr) or every 5yr. Diagnosis of higher-grade or -stage disease while on AS resulted in curative treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We measured discounted quality-adjusted life years (QALYs), discounted lifetime medical costs (2017 US$), and incremental cost-effectiveness ratios (ICERs). RESULTS AND LIMITATIONS:Compared to WW, MRI-based surveillance performed every 5yr improved quality-adjusted survival by 4.47 quality-adjusted months and represented high-value health care at the Medicare reimbursement rate using standard cost-effectiveness metrics. Biopsy-based strategies were less effective and less costly than the corresponding MRI-based strategies for each testing interval. MRI-based surveillance at more frequent intervals had ICERs greater than $800000 per QALY and would not be considered cost-effective according to standard metrics. Our results were sensitive to the diagnostic accuracy and costs of both biopsy modes in detecting clinically significant cancer. CONCLUSIONS:Incorporation of MRI into surveillance protocols at Medicare reimbursement rates and decreasing the intensity of repeat testing may be cost-effective options for men opting for conservative management of low-risk prostate cancer. PATIENT SUMMARY:Our study modeled outcomes for men with low-risk prostate cancer undergoing watchful waiting, immediate treatment, or active surveillance with different follow-up schedules. We found that conservative management of low-risk disease optimizes health outcomes and costs. Furthermore, we showed that decreasing the intensity of active surveillance follow-up and incorporating magnetic resonance imaging (MRI) into surveillance protocols can be cost-effective, depending on the MRI costs.