BACKGROUND: Abnormal microRNA (miRNA) expressions and promoter methylation of genes detected in sputum may provide biomarkers for non-small lung cancer (NSCLC). Here, we evaluate the individual and combined analysis of the two classes of sputum molecular biomarkers for NSCLC detection. RESULTS: We analyze expression of 3 miRNAs (miR-21, miR-31, and miR-210) and methylation of 3 genes (, , and ), which were previously identified as potential biomarkers for NSCLC, in sputum of a set of 117 stage I NSCLC patients and 174 cancer-free smokers. The results are validated in a different set of 144 stage I NSCLC patients and 171 controls. The panel of 3 miRNA biomarkers has 81.5 % sensitivity and 85.9 % specificity; the panel of 3 methylation biomarkers displays 82.9 % sensitivity and 76.4 % specificity for NSCLC detection. Integrated analysis of 2 miRNAs (miR-31 and miR-210) and 2 genes ( and ) yields higher sensitivity (87.3 %) and specificity (90.3 %) compared with the individual panels of the biomarkers ( < 0.05). Combined analysis of all the 3 miRNAs and 3 genes does not have performance superior to that of the panel of 2 miRNAs and 2 genes ( > 0.05). The performance of combined use of the two classes of biomarkers was confirmed in the validation set. CONCLUSIONS: The integration of two different classes of biomarkers synergistically improves both the sensitivity and the specificity for the early detection of NSCLC.