The stoloniferous hydrozoan Obelia geniculata frequently colonizes late-harvested blades of the aquacultured Saccharina japonica. To understand the corresponding changes at protein level, we compared the proteomic profiles in hydrozoan-colonized and healthy tissues. Our results showed that 107 and 75 protein spots were detected in colonized and healthy tissues, respectively. Among them, 7 and 16 identified proteins were significantly up- and down-regulated, respectively. Up-regulated proteins of cell-division cycle 46/minichromosome maintenance protein 5 and glutamyl-tRNA reductase were found mostly in hydrozoan-colonized tissues but were rare in healthy tissues. Microcompartments protein, carboxysome shell peptide, biotin synthetase, serine/arginine-rich splicing factor and a two-component response regulator were up-regulated in hydrozoan-colonized tissues. However, downregulated proteins of phosphoglycerate kinase, expansin 6, translation initiation factor 3, calcium/calmodulin-dependent protein kinase II inhibitor 2 and 50S ribosomal protein L1P were found mostly in healthy tissues but rare in hydrozoan-colonized tissues. Transmembrane protein, protoporphyrinogen oxidase, dual oxidase 2, PIH1 domain-containing protein 2, GTPase-activating protein alpha, threonyl-tRNA synthetase, flavanone 3-hydroxylase, uncoupling protein 3, bromoperoxidase 7, peptide release factor 1, and interaptin were down-regulated in hydrozoan-colonized tissues. Most of the up- and down-regulated proteins are known to be related to stress control, signal transduction and photosynthesis.