The solubility of water in tetradecyltrihexylphosphonium-based ionic liquids (ILs) with the bromide, bis(trifluoromethylsulfonyl)imide, bis(2,4,4-trimethylpentyl)phosphinate, chloride, decanoate, and dicyanimide anions was measured at temperatures between (288.15 and 318.15) K and atmospheric pressure. The effect of the nature of the IL anion, as well as the influence of temperature, are analyzed and discussed. From the experimental results, it was found that the anion-induced hydrophobicity increases from bis(2,4,4-trimethylpentyl)phosphinate < decanoate < chloride < bromide < dicyanimide < bis(trifluoromethylsulfonyl)imide. COSMO-RS, a predictive method based on unimolecular quantum chemistry calculations, was used to predict the solubility of the water−IL binary systems. COSMO-RS was found to provide fine qualitative and quantitative predictions of the experimental data for extremely hydrophobic ILs. Less accurate predictions were observed with the increase of the anion hydrophilic character.