KRASmutations occur in ∼35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway.KRASmutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and renderKRAS-mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here thatKRASG13-mutated cancer cells are frequently comutated withNF1GAP butNF1is rarely mutated in cancers withKRAScodon 12 or 61 mutations. Neurofibromin protein (encoded by theNF1gene) hydrolyzes GTP directly in complex with KRAS G13D, andKRASG13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Structures of the wild type and G13D mutant of KRAS in complex with neurofibromin (RasGAP domain) provide the structural basis for neurofibromin-mediated GTP hydrolysis. These results reveal that KRAS G13D is responsive to neurofibromin-stimulated hydrolysis and suggest that a subset ofKRASG13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.