OBJECTIVE: To evaluate the presence of L-myc gene variations as a genetic predisposition to head and neck nonmelanoma skin cancer (HNNMSC) and lower lip cancer (LLC). DESIGN: A case-control study. SETTING: An academic institute laboratory. PARTICIPANTS: Twenty-four patients with HNNMSC and 27 with LLC were compared with 51 age- and sex-matched control subjects. MAIN OUTCOME MEASURES: Polymerase chain reaction restriction fragment length polymorphism and agarose gel electrophoresis were used to determine the L-myc oncogene genotypes. RESULTS: The presence of the LS genotype was found to be significantly increased in the study group, whereas the LL genotype was not detected. The S allele was also more frequent in the study group. The SS genotype was found to correlate with aggressive tumor behavior in patients with HNNMSC and a family history of cancer. Patients with LLC displayed significantly less of the SS genotype. CONCLUSIONS: The L-myc gene polymorphism may help detect and prevent HNNMSC and LLC in susceptible individuals. It may also contribute to estimation of tumor behavior in patients with HNNMSC.