Expression of DNA repair genes was studied in uveal melanoma (UM) in order to identify genes that may play a role in metastases formation. We searched for genes that are differentially expressed between tumors with a favorable and unfavorable prognosis. Gene-expression profiling was performed on 64 primary UM from the Leiden University Medical Center (LUMC), Leiden, The Netherlands. The expression of 121 genes encoding proteins involved in DNA repair pathways was analyzed: a total of 44 genes differed between disomy 3 and monosomy 3 tumors. Results were validated in a cohort from Genoa and Paris and the The Cancer Genome Atlas (TCGA) cohort. Expression of the , , , and genes was significantly associated with clinical outcome after validation. was highly expressed in metastasizing UM ( < 0.001), whereas , , and were lowly expressed ( < 0.001, = 0.006, = 0.003, respectively). Low expression of and was related to a large tumor diameter ( = 0.01 and = 0.004, respectively), and a mixed/epithelioid cell type ( = 0.007 and = 0.03, respectively). We conclude that the expression of , , and is significantly lower in UM with an unfavorable prognosis, while these tumors have a significantly higher expression of . Pharmacological inhibition of DNA-PKcs resulted in decreased survival of UM cells. may be involved in proliferation, invasion and metastasis of UM cells. Unraveling the role of DNA repair genes may enhance our understanding of UM biology and result in the identification of new therapeutic targets.