Environmental pollution has resulted in the use of organo-tin and organo-copper compounds as antifouling agents being prohibited. Non-toxic natural products are considered to be environmentally friendly antifouling agents. Several phloroglucinol compounds isolated from three species of Eucalyptus have demonstrated strong attachment-inhibiting activity against the blue mussel. In this paper, we discuss the structure-activity relationship of these phloroglucinol compounds on the basis of molecular mechanics calculations. When these compounds were superimposed on each other and the strongest inhibitor was applied as a template, the repulsion energy of the other compounds was proportional to the logarithmic attachment-inhibiting activity. It is concluded that, of the two phloroglucinol rings in sideroxylonal A, ring C is more important, and those compounds that stereochemically and electrostatically resemble the template molecule are more active.