Equilibrium partition coefficients of organic chemicals from water to an organism or its tissues are typically estimated by using the total lipid content in combination with the octanol–water partition coefficient (K_ow). This estimation method can cause systematic errors if (1) different lipid types have different sorptive capacities, (2) nonlipid components such as proteins have a significant contribution, and/or (3) K_ow is not a suitable descriptor. As an alternative, this study proposes a more general model that uses detailed organism and tissue compositions (i.e., contents of storage lipid, membrane lipid, albumin, other proteins, and water) and polyparameter linear free energy relationships (PP-LFERs). The values calculated by the established PP-LFER-composition-based model agree well with experimental in vitro partition coefficients and in vivo steady-state concentration ratios from the literature with a root mean squared error of 0.32–0.53 log units, without any additional fitting. This model estimates a high contribution of the protein fraction to the overall tissue sorptive capacity in lean tissues (e.g., muscle), in particular for H-bond donor polar compounds. Direct model comparison revealed that the simple lipid-octanol model still calculates many tissue-water partition coefficients within 1 log unit of those calculated by the PP-LFER-composition-based model. Thus, the lipid-octanol model can be used as an order-of-magnitude approximation, for example, for multimedia fate modeling, but may not be suitable for more accurate predictions. Storage lipid-rich phases (e.g., adipose, milk) are prone to particularly large systematic errors. The new model provides useful implications for validity of lipid-normalization of concentrations in organisms, interpretation of biomonitoring results, and assessment of toxicity.