Quercetin is a flavonoid with high antioxidant activity, conceivably useful for pharmaceutical and cosmetic applications. Additionally, its molecular structure is potentially suited to stabilize emulsions. In this work the interaction of quercetin with cationic and nonionic surfactants in a mixed-surfactant bioactive nanoemulsion was investigated. The high-loaded quercetin nanoemulsion (prepared with 0.5% wow and entrapment efficiency of 99.8%), prepared by the sub-PIT method, was assessed in terms of thermal/photostability and safety for cosmetic applications. It proved to be highly stable to chemical degradation under ambient or sub-ambient storage conditions and very photostable to UV artificial radiation. Results of UV absorption/emission spectroscopy, differential scanning calorimetry and confocal fluorescence microscopy studies showed that in the nanoemulsion: (i) quercetin appears, mainly in the form of a neutral non-emissive 5OH hydrogen bonded tautomer with a minor population of both the emissive 3OH hydrogen bonded tautomer and the mono-anionic form; (ii) quercetin is very stable under UV radiation. (iii) quercetin interacts with the surfactants and is predominantly located at the oil/water interface of the nanodroplets. In contrast, when present in a coarse emulsion quercetin is preferentially dispersed in the aqueous phase. The nanoemulsion showed an excellent biocompatibility with skin, a low eye irritancy potential (HET-CAM assay). This favorable safety profile coupled with the high antioxidant content and thermal/photophysical stability, suggests a large potential of the quercetin nanoemulsion studied in this work for skin care applications. (C) 2016 Elsevier B.V. All rights reserved.