The rice root-knot nematode (Meloidogyne graminicola) is one of the most destructive pests threatening rice (Oryza sativaL.) production in Asia; however, no rice resistance genes have been cloned. Here, we demonstrate thatM. GRAMINICOLA-RESISTANCE GENE 1(MG1), anRgene highly expressed at the site of nematode invasion, determines resistance against the nematode in several rice varieties. IntrogressingMG1into susceptible varieties increases resistance comparable to resistant varieties, for which the leucine-rich repeat domain is critical for recognizing root-knot nematode invasion. We also report transcriptome and cytological changes that are correlated with a rapid and robust response during the incompatible interaction that occurs in resistant rice upon nematode invasion. Furthermore, we identified a putative protease inhibitor that directly interacts with MG1 duringMG1-mediated resistance. Our findings provide insight into the molecular basis of nematode resistance as well as valuable resources for developing rice varieties with improved nematode resistance.