In this communication, a novel one-pot synthetic strategy for preparing hollow PNIPAM microspheres via an interfacial polymerization approach at the interface of an inverse W/O emulsion has been proposed and demonstrated. The results show that the prepared PNIPAM microspheres have real empty core and polymer shell structure, with a size range of 1-3 mum. The hollow microspheres experienced a reversible swelling and deswelling process by mediating the temperature below and above the lower critical solution temperature (LCST) of the PNIPAM. The new approach not only provided a unique technical pathway to prepare hollow PNIPAM microspheres in situ under mild reaction conditions but also opened a platform for helping to understand the mechanism of diffusion, migration of the PNIPAM at an oil/water interface above its LCST, and the polymer layer formation mechanism as well.