To analyze the clinical and prognostic value of neuron specific enolase (NSE) levels in serum of advanced lung cancer patients, we analyzed serum NSE level of 110 advanced lung cancer patients (case group), 100 benign lung disease patients (benign disease group), and 100 healthy persons (control group). Case group patients were divided by NSE level into ≥25 ng/mL (52 cases) and <25 ng/mL (58 cases) groups to analyze overall survival (OS) and progression-free survival (PFS). The results showed the serum NSE levels of case group patients were significantly higher than those of control or benign disease group patients (P<0.05). Serum NSE levels of small cell lung cancer patients were significantly higher than those of patients with other tumor pathologies (all P<0.05). Median OS significantly differed between patients with NSE levels ≥25 ng/mL (23.7 months) and <25 ng/mL (31.4 months) (P<0.05). Median PFS also significantly differed between patients with NSE levels ≥25 ng/mL (13.5 months) and <25 ng/mL (17.6 months) (χ (2)=9.992; P<0.05). Tumor pathology (RR=4.136), patient performance status score (RR=2.903), and serum NSE level (RR=2.338) were factors influencing OS (P<0.05). Patient performance status score (RR=2.903), number of chemotherapy lines (RR=1.776), and serum NSE level (RR=2.075) were influencing factors in patients' PFS (P<0.05). In brief, serum NSE level significantly correlates with advanced lung cancer patient prognosis and may be useful as an auxiliary index to predict prognosis.