Circulating tumor cells (CTCs) are valuable for diagnosis, monitoring therapy and prognosis in primary lung cancer. Herein, we evaluated the clinical significance of lung cancer CTCs in this study. Detection of CTCs was performed using epithelial cell adhesion molecule-independent enrichment and CD45 fluorescence in situ hybridization detection. CTCs ≥ 2/3.2 mL were considered as positive. The positive rates in primary lung cancer, benign lung disease and healthy control groups were 84, 0 and 4.2 %. CTCs count was significantly higher in lung cancer patients than healthy controls and benign lung disease, with an area under ROC curve of 0.917 (95 % confidence interval 0.855-0.979; p = 0.000) between lung cancer and nonmalignant diseases. CTCs count significantly increased with an increase in pathological stage with mean count of 2.3 ± 2.6 (stage I-II), 3.5 ± 3.3 (stage III) and 4.5 ± 4.3 (stage IV), respectively. The positive detection rate of CTCs for primary lung cancer diagnosis was higher than serum tumor markers. In total, 25 metastasis lung cancer patients participated in the follow-up. Changes in CTCs count after two cycles of chemotherapy were consistent with radiographic appearance. Moreover, CTCs count was better than serum tumor markers for monitoring chemotherapy response. Median progression-free survival (PFS) was 2.05, 3.25 and 8.348 months (p < 0.05) in group in which post-treatment CTCs count was increased, unchanged and decreased, respectively. Furthermore, PFS in patients whose post-treatment CTCs count increased or were unchanged accompanied by a baseline CTCs count ≥3 was significantly shorter than those whose post-treatment CTCs count decreased or was unchanged accompanied with baseline value C < 3 (1.85 vs. 8.22 months, p = 0.000) [Corrected]. Therefore, CTCs are a reproducible indicator of disease status that may be superior to imaging.