The present study was undertaken to examine CYP1A1 and XRCC1 polymorphisms as potential genetic susceptibility markers for laryngeal squamous cell carcinoma (SCC). Eighty-eight patients with laryngeal SCC and 178 randomly selected healthy blood donors from the same Caucasian population (Porto, Northern Portugal) were analysed for CYP1A1 (MspI and NcoI) and XRCC1 (Arg194Trp and Arg399Gln) polymorphisms, using PCR-RFLP techniques. CYP1A1 MspI MH (mutant homozygous) and CYP1A1 NcoI HT (heterozygous) genotypes were more frequent in patients than in controls, with those carrying a CYP1A1 NcoI HT genotype having a 2.3-fold higher risk for tumour development. On the other hand, polymorphisms in XRCC1 codon 399 and codon 194 do not seem to play a role in the aetiology of smoking-related laryngeal SCC, once its distribution was similar in both analysed groups. All the significant associations observed were exclusively due to differences between controls and larynx glottic cancer patient subgroup. Furthermore, lower lifetime tobacco consumption was observed in laryngeal SCC patients carrying the MspI and NcoI polymorphisms, than in those who did not show the polymorphic variants. This investigation seems to support the importance of CYP1A1 gene polymorphism as a potential genetic marker of laryngeal cancer development, specially concerning smokers who have inherited the at-risk genotypes CYP1A1 MspI MH or CYP1A1 NcoI HT, who do appear to be more susceptible to the development of SCC of the glottic larynx.