Recent advances in the characterization of the lung cancer genome have suggested that KRAS may frequently be amplified, although little is known regarding the significance of this finding. This is in contrast with activating mutations of KRAS, which occur in approximately 20% of non-small cell lung carcinomas (NSCLCs). We used fluorescence in situ hybridization to provide direct evidence of KRAS amplification for the first time in clinical specimens. We detected amplification in 7 of 100 consecutive NSCLCs, with a concurrent activating KRAS mutation in 4 cases. KRAS amplification was associated with greater expression of p21 as assessed by quantitative immunohistochemical analysis (P = .015). Our data indicate that a sizable subgroup of NSCLCs harbor KRAS amplification, some of which also contain point mutations, and suggest that an increased KRAS copy number may drive p21 overexpression. KRAS amplification may define a unique clinicopathologic subset of NSCLCs with potentially altered responsiveness to targeted therapies.