BACKGROUND Economic analyses of new technologies, such as proton‐beam radiotherapy (PBT), are a public health priority. To date, no systematic review of the cost‐effectiveness of PBT has been performed. METHODS Systematic searches of PubMed, EMBASE, s from American Society for Radiation Oncology and American Society of Clinical Oncology meetings, and the Cost‐Effectiveness Analysis Registry were conducted (2000‐2015) along with s from the Particle Therapy Co‐Operative Group of North America for both years of existence (2014‐2015). Eighteen original investigations were analyzed. RESULTS The cost‐effectiveness for prostate cancer—the single most common diagnosis currently treated with PBT—was suboptimal. PBT was the most cost‐effective option for several pediatric brain tumors. PBT costs for breast cancer were increased but were favorable for appropriately selected patients with left‐sided cancers at high risk of cardiac toxicity and compared with brachytherapy for accelerated partial breast irradiation. For non‐small cell lung cancer (NSCLC), the greatest cost‐effectiveness benefits using PBT were observed for locoregionally advanced—but not early stage—tumors. PBT offered superior cost‐effectiveness in selected head/neck cancer patients at higher risk of acute mucosal toxicities. Similar cost‐effectiveness was observed for PBT, enucleation, and plaque brachytherapy in patients with uveal melanoma. CONCLUSIONS With greatly limited amounts of data, PBT offers promising cost‐effectiveness for pediatric brain tumors, well‐selected breast cancers, locoregionally advanced NSCLC, and high‐risk head/neck cancers. Heretofore, it has not been demonstrated that PBT is cost‐effective for prostate cancer or early stage NSCLC. Careful patient selection is absolutely critical to assess cost‐effectiveness. Together with increasing PBT availability, clinical trial evidence, and ongoing major technological improvements, cost‐effectiveness data and conclusions from this analysis could change rapidly. Cancer 2016;122:1483–501. © 2016 American Cancer Society. In the face of economically changing landscapes of health care reform, having evidence‐based justification of new technologies, such as proton radiation therapy, is crucial. The authors demonstrated that this modality is not the most cost‐effective option for prostate or early‐stage lung cancers; however, it is the most cost‐effective for several pediatric cancers and remains favorable for some left‐sided breast cancers, locoregionally advanced lung cancers, and select head/neck cancers.