Nucleotide excision repair (NER) and base excision repair (BER) pathways are DNA repair pathways that are important in carcinogenesis and in response to DNA-damaging chemotherapy. ERCC1 and ERCC2 are important molecular markers for NER; XRCC1 and PARP1 are important molecular markers for BER. Functional polymorphisms have been described that are associated with altered expression levels of these genes and with altered DNA repair capability. We assayed genomic DNA from 156 Americans of European descent and 164 Americans of African descent for the allelic frequencies of specific polymorphisms of ERCC1 N118N (500C > T), ERCC1 C8092A, ERCC2 K751Q (2282A > C), XRCC1 R399Q (1301G > A), XRCC1 R194W (685C > T), and PARP1 V762A (2446T > C). Differences were observed between Americans of European descent and Americans of African descent in the allelic frequencies of the ERCC1 N118N polymorphism (P < 0.000001). Differences were also observed between these two ethnic groups for ERCC2 K751Q (P = < 0.006675), XRCC1 R399Q (P < 0.000001), and PARP1 V762A (P = 0.000001). The ERCC1 N118N polymorphic variant that is seen most commonly in Americans of European descent is associated with a measurable reduction in NER function. ERCC1-mediated reduction in NER functionality affects the repair of cisplatin-DNA lesions.