We examined the p53 status of 108 NSCLCs compared to the expression of MLH1 and MSH2 proteins. p53 overexpression was demonstrated by IHC in 64% of patients examined, whereas p53 mutations were detected in 43%. Twenty-two percent of mutations were located outside of the hot-spot (exons 5–8) area. p53 mutations and overexpression were more frequent in SCCL (57% and 73%, respectively) than in lung adenocarcinomas (22% and 50%, respectively). In NSCLC-carrying wild-type p53, increased expression of MSH2 correlated with p53 overexpression (p = 0.018). In addition, in SCCL, p53 mutations correlated with reduced MSH2 expression (p = 0.019). These data suggest a relationship between p53 and MSH2. While there is evidence for p53 being a transcriptional activator of MSH2, the hypothesis that MSH2 acts as a DNA-damage signaller triggering p53 overexpression needs to be clarified in future studies. © 2002 Wiley-Liss, Inc.