The hydration thermodynamics of different mutants of α-synuclein (α-syn) related to familial Parkinson's disease (PD) is explored using a computational approach that combines both molecular dynamics simulations in water and integral equation theory of molecular liquids. This analysis focuses on the change in conformational entropy, hydration free energy (HFE), and partial molar volume of α-syn upon mutation. The results show that A53T, A30P, E46K, and H50Q mutants aggregate more readily and display increased HFE and less negative interaction volume than the wild-type α-syn. In contrast, an opposite trend is observed for the G51D mutant with a lower experimental aggregation rate. The residuewise decomposition analysis of the HFE highlights that the dehydration/hydration of the hydrophilic residue-rich N- and C-termini of α-syn majorly contributes to the change upon mutation. The hydration shell contributions of different residues to the interaction volume are consistent with its increase/decrease upon mutation. This work shows that both HFE and interaction volume determine the aggregation kinetics of α-syn upon mutation and may serve as an appropriate benchmark for the treatment of PD.