Diverse strains of the marine planktonic cyanobacteriumSynechococcussp. show consistent differences in their susceptibility to predation. We used mutants of Sargasso Sea strain WH8102 (clade III) to test the hypothesis that cell surface proteins play a role in defence against predation by protists. Predation rates by the heterotrophic dinoflagellateOxyrrhis marinaon mutants lacking the giant SwmB protein were always higher (by 1.6 to 3.9×) than those on wild-type WH8102 cells, and equalled predation rates on a clade I strain (CC9311). In contrast, absence of the SwmA protein, which comprises the S-layer (surface layer of the cell envelope that is external to the outer membrane), had no effect on predation byO. marina. Reductions in predation rate were not due to dissolved substances inSynechococcuscultures, and could not be accounted for by variations in cell hydrophobicity. We hypothesize that SwmB defendsSynechococcusWH8102 by interfering with attachment of dinoflagellate prey capture organelles or cell surface receptors. Giant proteins are predicted in the genomes of multipleSynechococcusisolates, suggesting that this defence strategy may be more general. Strategies for resisting predation will contribute to the differential competitive success of differentSynechococcusgroups, and to the diversity of natural picophytoplankton assemblages.