Fat-free mass hydration, the ratio of total body water (TBW) to fat-free mass (FFM), is stable at approximately 0.73 in mammals, and this constancy provides a means of estimating total body fat in vivo. As there is no mechanistic theory to explain the magnitude and variability in TBW/FFM, the present investigation describes a cellular-level model indicating that FFM hydration is determined by four factors: body cell mass hydration, extracellular fluid hydration, ratio of extracellular solids to TBW, and ratio of extracellular water to intracellular water. According to the model, TBW/FFM can be predicted for adult humans as a mean of 0.73, and a variation range 0.69-0.77. The suggested modeling approach provides a conceptual framework for TBW-fat estimation method and identifies important areas that remain to be studied.