A novel series of fluorine-containing thermo-sensitive core/shell microgel particels, poly[N-isopropylacrylamide-co-2,2,3,4,4,4-Hexafluorobutyl methacrylate-co-Poly(ethylene glycol) methyl ether methacrylate] [P(NIPAAm-co-HFMA-co-MPEGMA)], were prepared via surfactant free emulsion polymerization. The composition of the copolymer microgels was characterized by FTIR, 1H NMR, and 19F NMR. Subsequently, the thermo-responsive behavior of the microgels was studied by UV–vis spectroscopy, fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. The copolymer microgels exhibited a lower critical solution temperature (LCST) above the normal human physiological temperature. When the temperature was above the LCST, the hydrophobicity of the microgels increased significantly, and the average hydrodynamic diameter decreased greatly. TEM results showed that the copolymer microgels formed loose core–shell spherical particles below the LCST, but above the LCST, the particles became compact and the core–shell structure was not obvious. The drug loading and in vitro release were studied with 5-fluorouracil as a model drug. The result showed that the rate and amount of the drug release became much higher above the LCST. In a word, the study indicated that the fluorine-containing thermo-sensitive copolymer microgels had promising potential applications as a “smart” drug carrier in biomedical field.Graphical abstractA novel series of fluorine-containing thermo-sensitive core/shell microgel particles were prepared via surfactant free emulsion polymerization. The copolymer microgels exhibited a lower critical solution temperature (LCST) above the normal human physiological temperature. The size and morphology of the microgel particles were both sensitive to the change of temperature. Furthermore, the drug-loaded microgels showed a desired thermo-responsive drug release behavior. The study indicated that the fluorine-containing thermo-sensitive copolymer microgels had promising potential applications as a “smart” drug carrier in biomedical field.Highlights► We first prepared fluorine-containing thermo-sensitive core/shell microgels. ► The size and morphology of the microgels were sensitive to the temperature. ► The drug-loaded microgels showed a desired thermo-responsive drug release behavior. ► The microgels had potential applications as a controlled drug release carrier.