pH-responsive amphoteric core-shell microgel particles were synthesized by emulsion copolymerization of the appropriate functional monomers with ethylene glycol dimethacrylate as the cross-linker. 2-(Diethylamino)ethyl methacrylate (DEA) was used as the ionizable basic monomer, and tert-butyl methacrylate served as the hydrophobic monomer precursor, which gave the methacrylic acid (MAA) moieties following acid hydrolysis of the ester groups. The core of the polyampholyte microgels comprised a cross-linked poly(2-(diethylamino)ethyl methacrylate) (PDEA) or poly(methacrylic acid) (PMAA) network surrounded by a cross-linked PMAA or PDEA shell, respectively. A polyampholyte random copolymer microgel with the DEA and MAA units randomly distributed within the gel phase was also prepared. Scanning electron microscopy studies showed spherical particles of a narrow size distribution, and transmission electron microscopy verified the core-shell topology of the particles. Potentiometric titration curves revealed two plateau regions for the polyampholyte core-shell microgels attributed to the independent ionization process of the core and the shell of the particles, in contrast to the random copolymer microgel particles that exhibited a single plateau region as a result of the simultaneous protonation/deprotonation process of the basic and acidic moieties of the microgels. The core and the shell of the particles were found to swell independently upon ionization of the DEA or MAA moieties at low or high pH, respectively, whereas collapsed latex particles were obtained in the intermediate pH range when both the core and the shell of the particles were neutral, in agreement with the potentiometric titration data. These core-shell microgels comprise novel two-compartment nanostructure that exhibit contraphilic propel-ties in the core and the shell of the particles in response to a single external stimulus.