Muscle glycogen phosphorylase (GP) plays an important role in muscle functions. Mercury has toxic effects in skeletal muscle leading to muscle weakness or cramps. However, the mechanisms underlying these toxic effects are poorly understood. We report that GP is irreversibly inhibited by inorganic (Hg(2+)) and organic (CH3Hg(+)) mercury (IC50=380 nM and kinact=600 M.(-1).s(-1) for Hg(2+) and IC50=43 μM and kinact=13 M.(-1).s(-1) for CH3Hg(+)) through reaction of these compounds with cysteine residues of the enzyme. Our data suggest that the irreversible inhibition of GP could represent one of the mechanisms that contribute to mercury-dependent muscle toxicity.