2014 Background: ERCC1 is the lead enzyme in nucleotide excision repair of platinum-induced DNA adducts. The ERCC1 C8092Apolymorphism may lead to an altered capacity to regenerate chemotherapy-damaged normal tissue and greater treatment-related toxicity. METHODS Using logistic regression models, we evaluated the ERCC1 C8092Apolymorphism and its association with the occurrence of Grade III or IV toxicity in 147 locally advanced and metastatic NSCLC patients treated first-line with chest radiation and platinum-based chemotherapy. RESULTS Median age was 62 yrs; 50% were male; 93% had ECOG PS 0/1; 6% had inoperable early stage disease, 46% were stage IIIA, 39% were stage IIIB, and 9% were stage IV. Forty-two percent received cisplatin and 58% received carboplatin. Thirty-one (21%) patients experienced Grade III/IV GI toxicity (nausea, n=10; vomiting, n=4; esophagitis, n=20). After adjusting for type of platinum agent and PS, patients carrying at least one ERCC1 variant allele (C/A, A/A) were found to have an increased risk of GI toxicity compared to patients with the C/Cgenotype (see table), with similar results in a subgroup analysis on the 125 stage IIIA/B patients. Incidence of Grade III/IV toxicity from all causes was non-significantly increased in patients carrying the variant ERCC1allele (OR=1.84, 95% CI: 0.92-3.65, p=0.08). ERCC1 polymorphism was not associated with Grade III/IV hematologic toxicity (p=0.44). CONCLUSIONS Carrying at least one ERCC1 8092Aallele is associated with a greater than two-fold increase in Grade III/IV GI toxicity among NSCLC patients treated with chemoradiation. Supported by NIH grants CA074386, CA71345. [Figure: see text] No significant financial relationships to disclose.