ADAM28 (a disintegrin and metalloproteinase 28) is over-expressed in non-small cell lung cancer (NSCLC) with correlation to cancer proliferation, tumor size and lymph node metastasis. In the present study, we investigated the predictive and prognostic value of ADAM28 during chemotherapy in patients with advanced NSCLC. 122 advanced NSCLC cases, 37 patients with benign lung disease and 40 healthy controls were enrolled in the study. The serum levels of ADAM28 were measured by enzymelinked immunosorbent assays. Data were correlated with diagnosis, radiologic objective response and survival. Serum levels of ADAM28 in advanced NSCLC group were significantly elevated compared to benign lung disease group (P<0.001) and healthy controls (P<0.001). And the expression of ADAM28 had relationship to the tumor size and lymph metastasis in NSCLC patients. When the cut-off value of ADAM28 was 225.54 pg/ml, the area under the ROC curve was 0.843 (95% confidence interval [CI]: 0.784-0.902); the sensitivity (SEN) and specificity (SPE) were both the best, with a SEN of 76% and a SPE of 83%. The patients who had ADAM28-response and no ADAM28-response had significantly difference in objective response to treatment (P<0.001). The median Progression-free survival from response assessment was 5 months. In the multivariate analysis, performance status (hazard ratio [HR], 1.68; 95% CI: 1.06-2.67), the level of serum ADAM28 (HR, 1.01; 95% CI: 1.01-1.02), and ADAM28-responses (HR, 047; 95% CI, 0.26-0.83), were significant correlated with prognosis. The levels of ADAM28 and ADAM28-responses appeared to be reliable surrogate markers to predict tumor response and survival in patients with advanced NSCLC.