Methylated cyclodextrins were investigated to shed light on their solubility behavior in water where they exhibit a negative temperature coefficient, contrasting the positive temperature coefficient of unmodified cyclodextrins. Both heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TRIMEB) show two different conditions of crystallization. At low temperatures around IS degreesC, highly hydrated clathrates are formed, whereas, at high temperatures around 60-70 degreesC, DIMEB crystallizes as an anhydrate and TRIMEB as a monohydrate. The crystallization at high temperature is driven by entropy gain of water to compensate for the positive enthalpy change associated with this crystallization process, as could be shown by differential scanning calorimetry experiments in H2O and D2O.