DNA can oxidatively be deaminated by ROS, which converts DNA base amino groups to keto groups and can trigger abnormal mutations, resulting in mutagenesis in organisms. In this study, a noncanonical purine dNTP pyrophosphatase (AfPPase) from a hyperthermophilic archaeon Archaeoglobus fulgidus, which hydrolyzes aberrant nucleoside triphosphates, was overexpressed in E. coli, purified, and characterized. The purified AfPPase showed remarkably high activity for XTP and dITP, suggesting that the 6-keto group of these nucleotides is critical for the reactivity. Under optimal reaction conditions, the reaction rate for these substrates was about 120 times that with dGTP. Therefore, AfPPase may play a significant role in DNA repair by hydrolysis of noncanonical nucleotides before they are misincorporated into DNA.