Differentiation of malignant from benign pleural effusions is challenging in clinical practice due to limitations in the cytologic analysis. The combination of pleural fluid biomarkers has previously been used to predict malignant pleural effusion (MPE). We have conducted a prospective observational study to assess the diagnostic potential of cancer ratio [(CR) serum lactate dehydrogenase (sLDH): pleural fluid adenosine deaminase (pADA)], CR plus (CR: pleural lymphocyte count), sLDH: pleural lymphocyte count, and age: pADA in differentiating malignant effusions from benign ones. Prospective data from patients evaluated for exudative pleural effusions in the pulmonary medicine department at our institute over 12 months were collected. All subjects underwent thoracentesis, and if the results were inconclusive, they underwent invasive diagnostic testing for confirmation. They were divided into MPE and non-MPE groups for analysis. Pleural fluid biomarker ratios were calculated and compared between both groups, and receiver operating characteristic curves were generated. We included 120 subjects: 59 were diagnosed with MPE, and 61 had benign effusion (46 tubercular and 15 parapneumonic). The mean (standard deviation) age of the study population [64 (53.3%) males] was 52.4 (14.5) years. CR, CR plus, and age: pADA were significantly higher in the MPE group compared to the benign group. The sLDH: lymphocyte count was similar between both groups. Age: pADA ratio and CR performed best, with areas under the curve of 0.99 [95% confidence interval (CI), 0.97-1.0] and 0.97 (95% CI, 0.94-1.0) respectively. A higher age: pADA level was associated with a malignant etiology of effusion (adjusted odds ratio 12.27, 95% CI 2.37-63.54) on multivariate analysis. At a cut-off of 2, age: pADA ratio provided 96.6% sensitivity, 93.4% specificity, with a positive likelihood ratio of 14.7. Age: pADA and CR are promising diagnostic indices for differentiating MPE and non-MPE with high sensitivity and specificity. The diagnostic accuracy of CR plus and sLDH: lymphocyte ratio is inferior to that of CR and age: pADA.