An analysis of structural properties of the tryptophan-histidine (TRP-HIS) pair in vacuo and in various solvents (water, dimethyl sulfoxide, methanol, and carbon tetrachloride) has been done using classical molecular dynamics simulations with atomistic potential models for both solute and solvent molecules. The potential of mean force (PMF) was determined as a function of the TRP centroid-HIS centroid distance and of the angle between the ring planes. We show that T-shaped structures are favored in nonpolar solvents, whereas they are completely destabilized in solvents forming strong hydrogen bonds. Amphiphilic solvents such as methanol and dimethyl sulfoxide destabilize both the T-shaped and stacked arrangements. The results are consistent with previous analysis on protein crystallographic databases, where the stacked structures are found mainly on the protein surface exposed to the solvent, while T-shaped arrangements are preferentially found in the hydrophobic protein core. Finally, comparison of explicit solvent molecular simulation data and continuum solvent model results emphasizes the importance of microsolvation phenomena in shaping the potential of mean force for tryptophan-histidine interactions.