The oxidation-responsive behaviors of OEGylated poly-L-cysteine homopolypeptides, that is, poly(L-EG(x)MA-C)(n), were investigated. These poly-L-cysteine derivatives adopted mixed conformation in water, in which the beta-sheet accounted for a significant proportion. Upon oxidation, the thioethers in polypeptide side chains were converted to polar sulfone groups, which triggered the secondary structure transition from beta-sheet preferred conformation to random coil. Accordingly, the increase of side-chain polarity together with conformation changes increased samples' water solubility and cloud point temperature. Using mPEG(45)-NH2 as macroinitiator, we synthesized PEG(45)-b-poly(L-EG(2)MA-C)(22) diblock copolymer via ring-opening polymerization (ROP) of L-EG(2)MA-C N-carboxyanhydride (NCA). The PEG(45)-b-poly(L-EG(2)MA-C)(22) was able to self-assemble into spherical micelles in aqueous solution, and the micelles could undergo an oxidation-triggered disassembly due to the oxidation-responsive thioethers. Such a new class of oxidation-responsive polypeptides might provide a promising platform to construct inflammation targeting drug delivery systems.