This review summarized comparative clinical outcomes between proton and photon radiotherapy. 63 interventional comparative studies were presented in this analysis, including 6 randomized studies (1 prostate, 3 lung, 1 esophagus, 1 adult CNS) and 57 non-randomized reports (8 prostate, 3 breast, 9 lung, 8 esophagus, 7 head and neck, as well as 4 adult and 18 pediatric CNS cancers). The evidence of value is not definitive and further demonstration of the clinical benefit of proton therapy will depend on the findings of ongoing and future comparative randomized clinical trials.