Fish oil microcapsules were prepared using two natural polysaccharides, alginate and chitosan, as the wall materials. A response surface methodology (RSM) was used to optimize the conditions for fish oil encapsulation efficiency (FOEE). The FOEE was investigated with respect to three key-variables in the RSM: ratio of inner oil phase to aqueous phase (X-1, w/w); concentration of the aqueous phase (X-2, wt%); and ratio of the aqueous phase to outer oil phase (X-3, v/v). The optimal, formulation obtained from the RSM model, i.e., 2.7:1 (X-1), 1.6 wt% (X-2), and 11.5:1 (X-3), gave a FOEE of 28%. The model was validated and the fish oil microcapsules prepared under the optimized conditions were characterized in terms of particle size, polydispersity index (PDI), zeta potential, surface morphology, and in vitro release. The average droplet size, PDI, and zeta potential were 915 nm, 0.038, and +5.2 mV, respectively. The fish oil microcapsules were highly uniform microspheres, and had an accumulative release rate of 77.7% in 270 min in a gastrointestinal model, indicating their potential as an alternative carrier for the controlled release of fish oil. In conclusion, formulating optimal microencapsulation conditions by the RSM can be applied to the microencapsulation of various oil-soluble nutrients for food applications. (C) 2016 Chinese Society of Particuology and Institute of Process Engineering, Chinese Academy of Sciences. Published by Elsevier B.V. All rights reserved.