This paper describes a series of simulations using pressure as a tool to study the hydrophobic interaction between two simple solutes. The change in the free energy of association (Delta Delta G(r)) of the solutes as a function of pressure is expressed in terms of the change in partial molar volume (Delta V degrees) and the change in isothermal compressibility (Delta kappa degrees) of the system. At 30 degrees C, Delta V degrees is found to be -7.4 +/- 1.1 mL mol(-1), and Delta kappa degrees is found to be (-1.4 +/- 0.3) x 10(-3) mL mol(-1) bar(-1). The two effects are in opposition to each other : The volume term tends to favor solute association, while the compressibility term favors dissociation. The volume term is the dominant one in determining Delta Delta G(r) at moderate pressures. At higher pressures (above 5 kbar), the opposing effect becomes dominant. A new analysis of experimental data concerning pressure-dependent effects in the association constants for a series of carboxylic acids (Suzuki, K.; Taniguchi, Y.; Watanabe, T. J. Phys. Chem. 1973, 77, 1918-1922) lends support for these conclusions. The applicability of these results to understanding protein stability is discussed. The compressibility change provides an explanation for the pressure-induced denaturation of some proteins.