Background: Malignant Pleural Effusion (MPE) is a condition that mostly presents with dyspnea. There are some ways to distinguish it from NonMalignant Pleural Effusion (NMPE).The aim of this study was to compare serum and pleural D-dimer levels between MPE and NMPE patients. Materials and Methods: Patients diagnosed with Pleural Effusion (PE) were selected to participate in this study. They were allocated in 2 groups of MPE and NMPE according to the etiology. Serum and pleural fluid D-dimer level were measured and statistically analyzed between two groups. Results: 32 MPE patients and 32 NMPE patients participated in this study. The mean age was 61.3 ± 12 years and M/F ratio was 35/29. The mean pleural and serum D-dimer levels were 3472± 1312 ng/dl and 3259±1220 ng/dl in patients with MPE, and 3425 ± 32.5ng/dl and 2425 ± 1311ng/dl in patients with NMPE, respectively. The serum D-dimer levels were not statistically different between 2 groups; while the pleural D-dimer levels were higher in MPE group in comparison with NMP patients (p <0.05). Conclusion: This study showed that pleural D-dimer levels were significantly different between two groups and therefore pleural D-dimer can be considered as a non-invasive tool for diagnosis of MPE.