The aim of this study was to investigate the relation of HLA alleles in patients with non-small cell lung cancer (NSCLC). The incidence of class I and II HLA alleles of 63 patients with NSCLC were prospectively compared with the incidence of class I and II HLA alleles with 88 healthy controls. The number of cases with stage I and II (early stage) was 12 and there were 51 cases with stage III and IV (advanced stage). Metastasis rates of the regional lymph node in patients were as follow; N(0): n=10; N(1): n=13; N(2): n=26 and N(3): n=14. Lymph node metastasis was detected by pathological staging in 15 cases and by clinical staging in 48 cases. Lymph node metastasis was searched in all patients by a helical thorax CT. All distant metastasis were investigated by thorax CT, abdominal CT, brain CT or MRI and bone scintigraphy, and distant organ metastasis was detected in 25 cases. The patients and healthy controls were typed for HLA class I and II alleles. HLA-A2 was an independent risk factor for both critical lymph node (N(2 and 3)) involvement and distant metastasis. HLA-B44, -CW6 and -CW7 frequencies appear to be significant in controls compared to patients. HLA-A2 frequency was higher in patients with advanced stage than early stage, while HLA-A26, -B35 and -CW4 frequencies were more expressed in patients with early stage than in patients with advanced stage. Compared with controls, frequency of HLA-DRB1*07, -DQ02 and -DQ07 were lower expressed in patients. Compared patients with advanced stage, HLA-DRB1*07 was higher in patients with early stage. HLA-A2 was an independent risk factor for lymph node and distant metastasis, and the allele was significantly higher in patients with critical lymph node for surgery and distant metastasis. HLA-A26 appeared to be a significance protective allele against to metastases.