One of the most troublesome failures in head and neck tumors treatment is the incidence of multiple primary tumors (MPT). The aim of the study was to identity the genetic factors associated with the predisposition of second cancer occurrence. The polymorphisms of genes involved in carcinogen metabolic activation (CYP1A1, CYP2E1), detoxication (GSTM1, GSTT1, GSTM3, NAT2,) and DNA repair (XPD /A35931C-exon 23 and C22541A-exon 6/, XRCC1 /G28152A-exon 10 and C26304T-exon 6/, XRCC3/C18067T/) were studied by PCR-based techniques to analyze genotypes and allele distribution in 84 patients with MPT correlated with 182 subjects with a single tumor of head and neck and 143 cancer-free male volunteers recruited from healthy smokers. Out of 11 polymorphisms examined significant differences between studied groups in CYP1A1, GSTM1, NAT2 genes, but not at the CYP2E1, GSTT1, GSTM3, XPD (exon 23 and 6), XRCC1 (exon 10 and 6) and XRCC3 were established. Further, the coexistence of some genotypes/alleles associated with a higher cancer risk, so called 'risk genotypes' was established as an added genetic factor to MPT development. The interpretation of our data indicates that the same group of low-penetration genes is involved in the development of single and multiple primary head and neck cancer but their association with MPT is significantly stronger.