Based on the hypothesis that tissue partitioning of volatile organic compounds (VOCs) is due to lipophilic and hydrophilic interactions with tissue components, empirical relations are established between olive oil (P oil:air ), saline (P saline:air ), and tissue partition coefficients (P tissue:air ) for human and rat tissues. Reported values of partition coefficients of a wide range of VOCs with distinct chemical structures (n ؍ 137) have been compiled from the literature. Bilinear regression analysis shows that partition coefficients of VOCs in human blood, brain, fat, liver, kidney, and muscle tissues are well described by a linear combination of P oil:air and P saline:air with tissue-specific regression coefficients. The regression coefficient associated with the hydrophilic component of VOC partitioning in rat tissues is systematically higher than that of human tissues. For the human model, tissue concentrations calculated from predicted partition coefficients are generally within a factor 4 of tissue concentrations calculated from experimentally observed partition coefficients. These results demonstrate that, without prior knowledge of tissue composition, it is possible to obtain estimates of human tissue partition coefficients of VOCs with an accuracy that is in the same range as that commonly used in risk assessment.