A series of helicid analogues were synthesized and evaluated as tyrosinase inhibitors. The results demonstrated that some compounds had more potent inhibitory activities than arbutin (IC(50) 7.3 mM). In particular, compound 1c bearing 4,6-O-benzylidene substituent on the sugar moiety was found to be the most potent inhibitor with IC(50) value of 0.052 mM. The inhibition kinetics analyzed by Lineweaver-Burk plots revealed that helicid analogues were competitive inhibitors. The Circular dichroism spectra indicated that those compounds induced conformational changes of mushroom tyrosinase upon binding.