Diagnosis of malignant pleural effusion (MPE) remains a major clinical challenge. The aim of this study was to evaluate the diagnostic value of combined detection of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) and carcinoembryonic antigen (CEA) in patients with MPE and benign pleural effusion (BPE). The serum and pleural fluid samples were collected from 53 patients diagnosed with MPE and 49 patients with BPE. Enzyme-linked immunosorbent assay was used to detect the concentration of RCAS1 in serum and pleural effusion. The clinical data and laboratory information, including CEA levels, were gathered from these cases. The concentration of RCAS1 in MPE was significantly higher than that of BPE (P < 0.001). There was no significant difference between the two serum groups. The diagnostic sensitivity and specificity of pleural fluid RCAS1 were 67.92 and 81.63 %, respectively, at the optimized cutoff value of 7.326 U/mL; meanwhile, the sensitivity and specificity of pleural fluid CEA were 83.02 and 91.84 % at the cutoff value of 3.93 ng/mL. The specificity could be elevated to 98.50 % in serial detection, while the sensitivity may be improved to 94.55 % in parallel detection. Serum RCAS1 concentration was only detected in 53 serum samples out of the 102 samples, indicating that serum RCAS1 may not be a better option in differential diagnosis of malignancies compared with serum CEA, of which the diagnostic sensitivity and specificity were 64.15 and 83.67 % at the cutoff value of 3.90 ng/mL. No significant differences were found in pleural fluid RCAS1 concentration in MPE patients with different ages, gender, and pathological types of lung cancers. The detection of RCAS1 concentration in pleural fluid is informative for the diagnosis of MPE. Joint detection of RCAS1 and CEA can improve the diagnostic sensitivity and specificity. However, the diagnostic value of RCAS1 is not higher than that of CEA.