Light's criteria have classically been used to differentiate exudates from transudates. Nevertheless, a number of studies have attempted to identify more efficient parameters. The objective of our study was to determine the usefulness of biochemical parameters to differentiate transudates from exudates, and to compare them with the so far best studied criteria: the Light's criteria. We prospectively analysed 850 non selected cases of pleural effusion, with closed final diagnosis after its confirmation, therapeutic response and follow-up, collected consecutively at the Pleura Unit of our hospital. The parameters evaluated as potentially discriminatory between transudates and exudates included: glucose, proteins, albumin, lactate-dehydrogenase (LDH), cholesterol, triglycerides, bilirubin, alkaline phosphatase and adenosin-deaminase (ADA), both separately and in combination to obtain the highest yield. The highest diagnostic yield was observed with the combination of pleural cholesterol, pleural LDH, and the pleural fluid/serum protein ratio, but without significant differences between combinations of pleural cholesterol and LDH, pleaural LDH and pleural proteins, Light's criteria or modified Light's criteria. We recommend the use of pleural cholesterol higher than 47 mg/dl and pleural LDH higher than 222 IU/l to offer the same yield as the combination of three parameters, due to its lower cost and because the necessity of serum determinations is avoided.