Early detection of non-small cell lung cancer (NSCLC) cases is crucial since nearly one third of them are unresectable during diagnosis and also the recurrence rates are high following treatment. Thus, in this study we aimed to evaluate both the diagnostic performance and the post-resection progress of serum Human epididymis protein 4 (HE4) in patients with NSCLC. Thirty-one patients who had benign lung disease (group 1) were matched to the same number of patients with resectable NSCLC (group 2). Serum HE4 levels were measured at the time of diagnosis and following surgery - at post-operative 1st month (only in group 2). The serum HE4 in NSCLC group was significantly higher than that of the benign group (89.70 (58.10-397.00) pmol/L and 42.60 (28.10-198.90) pmol/L, respectively; p < 0.001). HE4 levels in NSCLC group were significantly decreased from 89.70 (58.10-397.00) to 71.50 (41.70-232.30) pmol/L following pulmonary resection (p < 0.001). In advanced stages (III and IV) the decrease in serum HE4 levels (25.30 (10.50-164.70) was significantly higher than the decrease in early stages (I-II, 14.60 (-14.20-133.60); p=0.025). ROC analysis showed the area under the curve (AUC) of HE4 was 0.921 (95% CI, 0.843-0.998), (p < 0.001) and both the sensitivity and specificity of HE4 as a biomarker was 87.1%. Our data demonstrated that HE4 is a potential biomarker for the diagnosis of NSCLC with high sensitivity and specificity and could also be used to detect recurrences following resection.