Increased risk of lung cancer has been reported in individuals with glutathione S-transferase M1 (GSTM1) gene deletion, with limited evidence for head and neck (HN) cancer. Here, we report the results of a case-control study in Japanese HN cancer patients (n = 158) and community controls (n = 174). GSTM1 null genotype (GSTM1(-)) was distributed more in smoker patients than in control subjects (56.7% vs. 48.5%) but not in non-smoker patients (48.3%). In smokers, GSTM1(-) was detected at increased frequency in non-larynx cancer (62.7%, odds ratio 1.77, 95% CI 1.04-3.01) but not in larynx cancer (48.1%). In larynx cancer GSTM1(-) was presented at higher frequency in patients < 60 years old than in those > or = 60 years old (78.6% vs. 36.8%). These findings suggest that the GSTM1 gene polymorphism potentially modifies the risk for HN cancer depending on smoking history, the region of cancer and age.