OBJECTIVES: To systematically review the currently available clinical and cost-effectiveness evidence on proton beam radiotherapy (PBRT) for cancers mostly affecting the eye: uveal melanoma, retinoblastoma and metastatic tumors. METHODS: A systematic literature search was conducted for published and unpublished cost-effectiveness and clinical data (comparative studies) on the eye cancer population, treated with proton radiation, using a number of medical databases (PubMed, EMBASE, Cochrane Library). In addition, clinical trial registries were searched, reference lists of included studies and of reviews were screened for missed studies. Searches took place in January 2012. RESULTS: The search generated 374 references, of which 5 comparative studies met the inclusion criteria. All were reporting cases of uveal melanoma. Studies were characterized by large differences in radiation techniques applied within the studies, and by variation in patient characteristics within and between studies. Overall, the level of evidence is low. When compared to iodine-125 or ruthenium-106 brachytherapy, protons did not provide beneficial effects on overall survival. Proton therapy was although superior to enucleation: results of two studies showed that 12% more patients survived over 36 months and 21% more patients survived over 60 months in the proton group. Vision preservation was observed significantly more frequently after proton therapy than iodine-125 brachytherapy (97% vs 93.1%, p=0.009). Only one included study reported side effects. Refractory neovascular glaucoma and corneal perforations were observed after proton therapy and 10.9% eyes treated with PBRT were enucleated due to complications. No economic evaluation studies were found. CONCLUSIONS: There is limited evidence on the effectiveness and safety of proton radiation in patients with ocular melanomas due to the lack of well-designed and well-reported studies. Available comparative studies suggest that proton beam therapy may be beneficial for patients with uveal melanoma, with, however, possible serious side effects. There is a need for research establishing its cost-effectiveness.