The objective of this study was to determine if area measurements of pleural fluid on computed tomography (CT) reflect the actual pleural fluid volume (PEvol) as measured at autopsy, to establish a formula to estimate the volume of pleural effusion (PEest), and to test the accuracy and observer reliability of PEest.132 human cadavers, with pleural effusion were divided into phase 1 (n=32) and phase 2 (n=100). In phase 1, PEvol was compared to area measurements on axial (axA), sagittal (sagA), and coronal (corA) CT images. Linear regression analysis was used to create a formula to calculate PEest. In phase 2, intra-class correlation (ICC) was used to assess inter-reader reliability and determine the agreement between PEest and PEvol. PEvol correlated to a higher degree to axA (r s mean= 0.738; p<0.001) than to sagA (r s mean=0.679, p<0.001) and corA (r s mean = 0.709; p < 0.001). PEest can be established with the following formula: axA×0.1=PEest. Mean difference between PEest and PEvol was less than 40 mL (ICC=0.837-0.874; p<0.001). Inter-reader reliability was higher between two experienced readers (ICC=0.984-0.987; p<0.001) than between an inexperienced reader and both experienced readers (ICC =0.660-0.698; p<0.001). Pleural effusions may be quantified in a rapid, reliable, and reasonably accurate fashion using single area measurements on CT.