Uveal melanoma (UM) is one of the most therapy-resistant cancers. Radiotherapy is the preferred treatment for most cases of UM. However, some UM cells, such as the SP6.5 or OM431 cell lines, are relatively radioresistant. In this study, we attempted to improve the current UM therapy using an adenovirus radio-inducible gene therapy system. The antitumor adenovirus was constructed by inclusion of the radiation-inducible early growth response gene 1 (EGR1) promoter and the anticancer tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. We demonstrated that the UM SP6.5 and OM431 cell lines were susceptible to the TRAIL-induced antitumor effect. TRAIL expression was enhanced in the adenovirus containing EGR1/TRAIL (Ad-ET) treatment group by radiotherapy, whereas Ad-ET significantly increased cell death and apoptosis caused by radiotherapy. In mice bearing xenograft tumors, apoptotic cells were detected in pathological tumor sections. Adenovirus Ad-ET combined with radiation therapy significantly inhibited tumor growth compared with the other treatment groups (P < 0.01). Our findings indicate that radioresponsive gene therapy has the potential to be a more effective and specific therapy for UM because the therapeutic gene can be spatially or temporally controlled by exogenous radiation.