Abstract: Objective:To investigate the possible role of miR-181d in regulating the multidrug resistance (MDR) of small cell lung cancer (SCLC) and its clinical significance. Methods:Quantitative reverse transcriptase- polymerase chain reaction (QRT- PCR) and Western blot were used to investigate the differential expression of miR-181d and BCL 2 from mRNA and protein levels in the chemo- sensitivity cell H69and the chemo- resistance cell H69AR. The miR- 181d expression in H69AR was then upregulated. More-over, CCK8 assay was employed to detect the sensitivities of the cells to chemotherapy drugs, such as ADM, DDP, and VP- 16. Mean -while, the expression of miR-181d in the specimens of 87cases with SCLC were detected using QRT- PCR. All patients received the chemotherapeutic regimen of EP (etoposide+cisplatin). Correlation of the miR-181d expression with clinicopathological features, prog -nosis, and survival time of the patients was studied. Results: miR-181d was downregulated in the SCLC multidrug-resistant cell line H69AR and chemo-resistant patients. Moreover, miR-181d was concurrent with the upregulation of BCL2 protein compared with the parental H69cell line and chemo- sensitive patients ( P<0.001). miR-181d expression in H 69cells resistant to chemotherapy drugs (ADM, DDP, and VP- 16) was inhibited (P<0.01). Enforced miR- 181d expression reduced the BCL 2 protein level and sensitized H69AR cells to chemotherapy drugs (P<0.01). miR- 181d expression was associated with tumor stage, sensitivity of chemotherapy, and survival time (all P<0.001). Patients with high miR- 181d expression had longer overall survival and progress-free survival time com -pared with those with low miR-181d expression ( P<0.001). Conclusion: miR-181d may play a role in the development of MDR in SCLC and may be a potential predictive factor for treatment efficacy.