Although the often profound effects of neutral salts on protein solubility were first identified over a century ago by Hofmeister, a general molecular explanation of these effects-capable of accounting even for salts with highly anomalous behavior-has yet to be established. As one way toward developing such an explanation, we aim here to quantify how eight simple monovalent salts alter the association thermodynamics of hydrophobic solute-pairs in a series of 1 its explicit-solvent molecular dynamics simulations. For both methane-methane and neopentane-neopentane associations, the salt-induced strengthening of the hydrophobic interaction observed in the simulations is found to be highly correlated with corresponding experimental solubility data; the computed changes in interaction free energy are also found to be quantitatively predictable using the preferential interaction formalism of Timasheff (Timasheff, S. N. Adv. Protein Chem. 1998, 51, 355-432). From additional simulations of 20 different pure salt solutions-in which no hydrophobic solutes are present-a strong correlation is also observed between the extent of water-water hydrogen bonding and experimental solubility data for hydrophobic solutes; this suggests that the Hofmeister effects of the simple salts investigated here may primarily be a manifestation of salt-induced changes in the water structure. Importantly, all of the strong correlations with experiment obtained here extend even to salts of lithium, whose unusual behavior has previously been unexplained; lithium's anomalous behavior can be rationalized in part by its formation of alternating, linear clusters (strings) with halide anions. The close agreement between simulation and experiment obtained in the present study reinforces previous work, showing that molecular simulations can be a valuable tool for understanding salt-related phenomena and indicating that this can be so even when the simulations employ the simple, nonpolarizable potential functions widely used in simulations of biological macromolecules.