We present in this work the first molecular simulation study of an enzyme, the serine protease cutinase from Fusarium solani pisi, in two ionic liquids (ILs): 1-Butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) and 1-Butyl-3-methylimidazolium nitrate  ([BMIM][NO3]). We tested different water contents in these ILs at room (298 K) and high temperature (343 K) and we observe that the enzyme structure is highly dependent on the amount of water present in the IL media. We show that the enzyme is preferentially stabilized in [BMIM][PF6] at 5-10% (w/w) (weight of water over protein) water content at room temperature. [BMIM][PF6] renders a more native like enzyme structure at the same water content of 5-10% (w/w) as previously found for hexane, and the system displays a similar bell-shape like dependence with the water content in the IL media. [BMIM][PF6] is shown to increase significantly the protein thermostability at high temperatures, especially at low hydration. Our analysis indicate that the enzyme is less stabilized in [BMIM][NO3] relative to [BMIM][PF6] at both temperatures, most likely due to the strong affinity of the [NO3]- anion towards the protein main chain. These findings are in accordance with the experimental knowledge for these two ionic liquids. We also show that these ILs “strip-off” most of the water from the enzyme surface in a similar degree as found for polar organic solvents such as acetonitrile, and that the remaining waters at the enzyme surface are organized in many small clusters.