Lung cancer is the leading cause of cancer related deaths. Despite the modern diagnostic and therapeutic advances, 5-year survival rate of all cases of lung cancer does not exceed 15%. Therefore, sensitive tumor biomarkers are needed for the early detection and differential diagnosis of lung cancer. The aim of the study was to evaluate the diagnostic efficiency of HE4 (Human epididymis protein 4) and CYFRA 21-1 in patients with lung cancer. Serum samples were collected from 80 patients; Group 1 consisted of 53 patients with lung cancer and Group 2 consisted of 27 patients as control. HE4 and CYFRA 21.1 levels were measured by chemiluminescent microparticle immunoassay (CMIA). The cut-off limits for HE4 was 70 pmol/L and 2 ng/mL for CYFRA 21-1. Serum mean HE4 levels in Group 1 (94.79 +/- 50.56 pmol/L) were significantly higher than that of Group 2 (52.00 +/- 21.06 pmol/L), (p < 0.001). CYFRA 21-1 levels in Group 1 and Group 2 were 5.15 +/- 7.89 ng/mL and 1.75 +/- 2.11 ng/mL, respectively (p = 0.004). The sensitivity rates were 73.5% for HE4 and 50.9% for CYFRA 21-1. Both tumor markers were clearly related to stage with significantly higher ratio of increase in advanced stages (III-IV) than in early stages (I-II), (p = 0.021 for HE4, p = 0.003 for CYFRA 21-1). HE4 and CYFRA 21.1 might be used as potential diagnostic markers for lung cancer patients. Especially HE4 may be candidate as a "leading-marker" for the discrimination of lung cancer because of its high sensitivity, positive predictive value and diagnostic accuracy.