Background: Lung cancer is the leading cause of cancer mortality in the world. Many factors can protect against or facilitate its development. A TNF family member TRAIL, has a complex physiological role beyond that of merely activating the apoptotic pathway in cancer cells. Vitamin D is converted to its active form locally in the lung, and is also thought to play an important role in lung health. Our goal was to investigate the possible clinical significance of serum sTRAIL and 1,25-dihydroxyvitamin D(3) levels in patients with non-small cell lung cancer (NSCLC). Materials and Methods: Totals of 18 consecutive adenocarcinoma and 22 squamous cell carcinoma patients with stage-IV non-small cell lung cancer referred to our institute were included in this study. There were 12 men and 6 women, with ages ranging from 38 to 97 (mean 60.5) years with adenocarcinoma, and 20 men and 2 women, with ages ranging from 46 to 80 (mean 65) years with squamous cell carcinoma. Serum levels of sTRAIL and 1,25-dihydroxyvitamin D(3) were measured in all samples at the time of diagnosis. Results: sTRAIL levels in NSCLC patients were higher than in the control group. Although there was no correlation between patient survival and sTRAIL levels, the highest sTRAIL levels were correlated with age and cigarette smoking in the adenocarcinoma patients. sTRAIL level in healthy individuals were correlated with serum 1,25-dihydroxyvitamin D(3). Conclusions: Serum sTRAIL concentrations were increased in NSCLC patients, and correlated with age and smoking history, but not with overall survival.