Studies have shown cell-free microRNA (miRNA) circulating in the serum and plasma with specific expression in cancer, indicating the potential of using miRNAs as biomarkers for cancer diagnosis and therapy. This study was to investigate whether plasma miRNA-21 (miR-21) can be used as a biomarker for the early detection of non-small cell lung cancer (NSCLC) and to explore its association with clinicopathologic features and sensitivity to platinum-based chemotherapy. We used real-time RT-PCR to investigate the expression of miR-21 in the plasma of 63 NSCLC patients and 30 healthy controls and correlated the findings with early diagnosis, pathologic parameters, and treatment. Thirty-five patients (stages IIIB and IV) were evaluable for chemotherapeutic responses: 11 had partial response (PR); 24 had stable and progressive disease (SD+ PD). Plasma miR-21 was significantly higher in NSCLC patients than in age- and sex-matched controls (P < 0.001). miR-21 was related to TNM stage (P < 0.001), but not related to age, sex, smoking status, histological classification, lymph node status, and metastasis (all P > 0.05). This marker yielded a receiver operating characteristic (ROC) curve area of 0.775 (95% CI: 0.681- 0.868) with 76.2% sensitivity and 70.0% specificity. Importantly, miR-21 plasma levels in PR samples were several folds lower than that in SD plus PD samples (P = 0.049), and were close to that in healthy controls (P = 0.130). Plasma miR-21 can serve as a circulating tumor biomarker for the early diagnosis of NSCLC and is related to the sensitivity to platinum-base chemotherapy.