High-resolution proton nuclear magnetic resonance (NMR) spectrometry of biofluids has been increasingly used in laboratory diagnosis of various diseases. In this study, we extended the use of (1)H NMR spectroscopy for laboratory diagnosis of exudative pleural effusions using pleural fluids. We compared this new NMR-based test with Light's criteria, the current gold standard for laboratory diagnosis of exudative pleural effusions. We analyzed 67 samples of pleural effusions from patients with pulmonary malignancy (N = 32), pulmonary tuberculosis (N = 18), and congestive heart failure (N = 17). The metabolomes of pleural effusions were analyzed using (1)H NMR spectroscopy on a Bruker 600 MHz spectrometer. Through a metabolome-wide association approach with filtering of insignificant markers (p value <4 × 10(-6)) and multivariate analysis (principal component analysis and orthogonal partial least squares-discriminant analysis), lipoprotein was found to be the best biomarker that distinguished exudates from transudates. Using NMR-based lipoprotein profiling to classify exudative pleural effusions from transudates, the area-under-receiver operating characteristic (ROC) curve was 0.96 with sensitivity of 98%, specificity of 88%, and accuracy of 98%. In contrast, the current gold standard, Light's criteria, give a specificity of only 65% at the same sensitivity level of 98%. Using the principle of size exclusion, NMR-based lipoprotein profiling of pleural fluids has an unprecedented diagnostic performance superiority over the Light's criteria. The capillary leaks secondary to inflammation result in a larger pleural pore-size, which allows the large-sized lipoproteins to accumulate in exudative pleural effusions. In contrast, the pleural permeability is intact in transudates, which allow only small-sized lipoproteins to pass into the pleural effusions. The average capillary pore-size of the pleura can therefore be determined by using NMR-based lipoprotein profiling of pleural fluids. We believe this new test will change the current clinical practice for management of pleural effusions and will become a new standard for clinical practice.