The level of Reactive oxygen species modulator1 (Romo1) and Carcinoembryonic Antigen (CEA) in malignant pleural effusion (MPE) were measured to explore their clinical diagnostic value. Methods We selected 57 cases with MPE and 60 cases with benign pleural effusion (BPE) for our study, included 68 male patients and 47 female patients, average, 62 (53.71)years, The BPE included 27 patients with Tuberculous pleural effusion, 22 patients with Parapneumonic Pleural Effusion and 11 patients with exudative pleural effusion, used enzyme-linked immunosorbent assay (ELISA) to measure the levels of Romo1 and CEA, drawn the Receiver operating characteristic curve (ROC) and calculated the sensitivity or specificity of Romo1 and CEA using SPSS software, to explore the diagnostic value of CEA and Romo1 alone or in combination for MPE. Results Pleural Romo1 and CEA levels were higher in patients with MPE than in patients with BPE (P＜0.05), No statistical significance was found in the BPE (P＞0.05). With a cut-off value of 113.69 pg/mL, the sensitivity, specificity, and area under the curve of Romo1 to diagnose MPE were 87.70%, 50%, and 0.736, With a cut-off value of 2858 pg/mL, the sensitivity, specificity, and area under the curve of Romo1 to diagnose MPE were 59.60%, 80%, and 0.731. CEA combined with Romo1 can improve diagnosis efficiency,the sensitivity, specificity, and area under the curve were 87.7%, 63.3%, 0.818. Conclusion The level of Romo1 in pleural effusion play a role in differential diagnosis of benign and malignant effusion. And its combination with pleural CEA increased the diagnostic performance.