BACKGROUND The objective of the current study was to determine whether tumor cells harboring P53 and K‐ras mutations could be detected in histopathologically tumor‐free surgical margins in patients with nonsmall cell lung carcinoma who underwent complete pulmonary resection. METHODS In 118 consecutive patients, DNA obtained from primary tumors and from surgical margins was extracted for molecular analysis. A fragment of P53 gene encompassing exons 5–8 and codon 12 of the K‐ras gene were amplified with the polymerase chain reaction technique and were assayed for the presence of mutations. RESULTS P53 and K‐ras mutations were found in 30% and 39% of primary tumors, respectively, and in 11 (9%) and 22 (18%) apparently tumor‐free surgical margins, respectively. At least 1 of those mutations was found in surgical margins in 29 patients (25%), and both mutations were found in 2 patients (1.7%). P53 mutations in surgical margins accompanied mutations in primary tumors in 9 of 35 patients (26%), and K‐ras mutations accompanied mutations in primary tumors in 20 of 46 patients (44%). Among patients with either mutation in primary tumors, the incidence of at least 1 mutation in surgical margins was 43% (28 of 65 patients). In four patients, mutations (two K‐ras mutations and two P53 mutations) were found in surgical margins despite the absence of the corresponding mutations in primary tumors. The presence of mutations in primary tumors and in surgical margins was not related significantly to clinical characteristics or to patient outcomes. CONCLUSIONS P53 and K‐ras mutations are frequent events in surgical margins determined to be tumor free on light microscopy. The clinical relevance of these findings remains to be established. Cancer 2004. © 2004 American Cancer Society.