The fluorescence of pyrene, a hydrophobic probe, was investigated in binary mixtures comprising a nonprotic [acetonitrile, NN-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and tetrahydrofurane (THF)] and a protic (water, methanol, ethanol, propan-2-ol, and butan-1-ol) solvent. The variation in I/III values, the intensity ratios between the first and third bands in vibronic fine structures of the emission spectra, along with the variation in the more polar component was studied for each binary mixture. A preferential solvation (PS) model was adapted from the literature and successfully applied to the experimental data. In the mixtures containing acetonitrile, pyrene is always preferentially solvated by the nonprotic component. However, the extent of PS by acetonitrile diminishes with a decrease in the polarity of the protic cosolvent. These results were explained by the fact that pyrene is a highly hydrophobic probe. Thus, a replacement of the more polar protic cosolvent for one which is more hydrophobic may lead to a comparatively stronger interaction of the probe with the cosolvent through hydrophobic interactions. Synergism was observed for binary mixtures comprising THF and the studied alcohols, for DMSO with water and methanol, and for DMF with water. Finally, D2O-DMF and D2O-DMSO mixtures were studied and compared with the corresponding H2O mixtures. It was verified that the extent of PS in both cases is diminished if water is replaced by deuterium oxide. All data were interpreted in terms of solute-solvent and solvent-solvent interactions.