Phagocytosis is a conserved cellular mechanism for food uptake, defense and general animal-microbe interactions in metazoans. How the discrimination and subsequent processing of native and foreign microbes is facilitated remains largely unknown in marine invertebrates. Thereto, we combined a recently developed phagocytic assay with proteomics analysis to compare the phagocytic activity of the sponge Halichondria panicea upon encounter with a native (i.e., isolated from H. panicea; Hal 281) and a foreign (i.e., isolated from Nematostella vectensis; NJ1) Vibrio isolate.