To assess whether DNA repair gene variants influence the clinical behaviour of lung cancer we examined the impact of a comprehensive panel of 109 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 50 DNA repair genes on overall survival (OS) in 700 lung cancer patients. Fifteen nsSNPs were associated with OS, significantly greater than that expected (P=0.04). SNPs associated with prognosis mapped primarily to two repair pathways—nucleotide excision repair (NER): ERCC5 D1104H (P=0.004); ERCC6 G399D (P=0.023), ERCC6 Q1413R (P=0.025), POLE (P=0.014) and base excision repair: APEX1 D148E (P=0.028); EXO1 E670G (P=0.007); POLB P242R (P=0.018). An increasing number of variant alleles in EXO1 was associated with a poorer prognosis [hazard ratio (HR)=1.24; P=0.0009]. A role for variation in NER and BRCA2/FA pathway genes as determinants of OS was provided by an analysis restricted to the 456 patients treated with platinum-based agents. Our data indicate that the pathway-based approach has the potential to generate prognostic markers of clinical outcome.