ABSTRACT Introduction Carcinogenesis is a complex process in which genomic instability is affected. The most important processes involved in DNA damage repair are the excision of defective bases - base excision repair (BER pathways) and the excision of the entire defective nucleotide – nucleotide excision repair (NER pathways). Two of the most important proteins involved in the BER and NER, respectively pathway are the X-ray cross-complementation group 1-XRCC1 and the Xeroderma pigmentosum group D protein-XPD Aim: to analyze the distribution of genetic polymorphisms in genes coding for DNA repair enzymes XPD (Lys751Gln) and XRCC1 (Arg399Gln) in Romanian patients with sporadic colorectal cancer (CCR) as compared to control subjects, both females and males; to establish the most frequent haplotype associated with sporadic CCR risk in Romanians; to check for the association with the different stages of carcinomas, as well as with the prognosis of sporadic CCR. Methods 312 samples were collected, of which 150 were sporadic CCR cases (80 female and 70 male patients) and 162 were controls (100 females and 62 males); Genotyped were done by PCR-RFLP analysis. The differences in genotype and allele frequencies between the group of patients with sporadic CCR and the control group were also examined using SPSS® Software version 12 for Windows (SPSS Inc., Chicago Illinois, USA 1989- 2003). Results The risk to develop sporadic CRC was 3.09 (p=0.02) and 3.49 (p=0.001), respectively, in association with the homozygous Gln/Gln-XPD and Gln/Gln-XRCC1 genotype. Also significantly higher risk to develop sporadic CRC was found in females homozygous for Gln/Gln-XPD (OR 3.43, p=0.04) and Gln/Gln-XRCC1 (OR 3.32, p=0.018) genotype and in males homozygous for Gln/Gln-XRCC1 (OR 3.63, p=0.04) genotype. The combined effect of the two polymorphisms on sporadic CRC risk was also evaluated through the construction of haplotypes. A significantly higher risk for sporadic CRC in association with Lys/Gln-Arg/Gln (22% vs. 7.4%, OR 3.52, p Conclusion Genetic variations affecting DNA repair capacity increase the risk for sporadic colorectal cancer in Romanians. The XPD and XRCC1 mutations could be associated with more aggressive forms of sporadic colorectal cancer and positive patients have a worse prognosis compared to negative patients.