The molecular mechanism of the conformational transition of amyloid peptide 42(Aβ42) inhibited by trehalose was studied using molecular dynamics simulation. It is confirmed that the conformational transition of Aβ42 is prevented by trehalose in a dose-dependent manner. In water and low-concentration trehalose (0.18 mol·L-1) solutions, Aβ42 transforms from its initial α-helix to a β-sheet. In 0.37 mol·L-1 trehalose, however, the conformational transition of Aβ42 is prevented. It is obvious that there is a hydration shell within about 0.2 nm from the closest atoms of Aβ42 on the peptide surface, which is caused by the preferential exclusion of trehalose. Trehalose molecules cluster around the peptide at a distance of 0.4 nm. In addition, the intra-peptide hydrophobic interactions are weakened and the number of long range contacts of Aβ42 is decreased by trehalose. Therefore, the hydrophobic collapse of the peptide is alleviated and the conformational transition is inhibited. These findings are important for the rational design of a highly efficient inhibitor for Alzheimer's disease.