The depletion force is described as an entropic force because it is fundamentally a manifestation of the second law of thermodynamics, which states that a system tends to increase its entropy. The gain in translational entropy of the depletants, owing to the increased available volume, is much greater than the loss of entropy from flocculation of the colloids. The positive change in entropy lowers the Helmholtz free energy and causes colloidal flocculation to happen spontaneously. The system of colloids and depletants in a solution is modeled as a canonical ensemble of hard spheres for statistical determinations of thermodynamic quantities.
However, recent experiments and theoretical models found that depletion forces can be enthalpically driven. In these instances, the intricate balance of interactions between the solution components results in the net exclusion of cosolute from macromolecule. This exclusion results in an effective stabilization of the macromolecule self-association, which can be not only enthalpically dominated, but also entropically unfavorable.