Aim: The differentiation of exudative from transudative effusion is important to lead the clinician in making further biochemical analysis for possible etiology and in choosing the appropriate treatment strategy. The aim of the study is to evaluate the diagnostic value of biochemical parameters together with Lights criteria to differentiate exudative from transudative effusions. Material and Method: The LDH, total protein, albumin, adenosine deaminase (ADA), apolipoprotein A1, apolipoprotein B, Lipoprotein-A, total cholesterol, HDL-cholesterol, VLDL-cholesterol, LDL-cholesterol, and triglyceride levels of patients with unknown etiology were measured both in plasma and pleural fluid. Mann-Whitney U was used to compare the groups and p < 0.05 was accepted as statistical significance. Sensitivity, specificity, and accuracy were calculated for each biochemical parameter. The ROC analysis was used to estimate the optimum cut-off value for the highest sensitivity and specificity. Results: Pleural LDH (p=0.001), total protein (p=0.001), albumin (p=0.001), triglyceride (p=0.001), total cholesterol (p=0.001), HDL-cholesterol (p=0.042), VLDL-cholesterol (p=0.001), LDL-cholesterol (p=0.001), apolipoprotein A1 (p=0.021), and HDL-cholesterol/LDL-cholesterol ratio (p=0.048) were found significant in differentiating exudative from transudative effusions. Discussion: The study showed that the use of pleural LDH, total cholesterol, and HDL-cholesterol levels together is more significant than Lights criteria. The sensitivity, specificity, and accuracy of this test were 99%, 94.1%, and 96.2% respectively.