AbstractBACKGROUNDThe treatment of lung cancer has reached a therapeutic plateau. Several mechanisms of platinum resistance have been described, including the removal of platinum‐DNA adduct by nucleotide excision repair (NER). Polymorphisms within the Xeroderma pigmentosum Group D protein (XPD), a member of the NER pathway, are associated with alterations in enzyme activity and may change sensitivity to platinum‐based chemotherapy. The authors investigated the relation between XPD polymorphisms and treatment response, toxicity, and overall survival in patients who received platinum‐based chemotherapy for advanced nonsmall cell lung cancer (NSCLC).METHODSBetween 2001 and 2002, 108 patients with chemotherapy‐naive, advanced NSCLC were recruited. Associations between XPD312/751 polymorphisms and XPD haplotype and treatment response, toxicity. and survival were evaluated.RESULTSSignificant correlations were observed between XPD haplotype and Grade 4 neutropenia and overall survival together with a greater response to platinum‐based chemotherapy for the XPD *A haplotype.CONCLUSIONSThe XPD haplotype may represent a useful pharmacogenomic marker of platinum‐based chemotherapy in patients with advanced NSCLC and requires prospective validation. Cancer 2006. © 2006 American Cancer Society.