The sarcoplasmic reticulum membrane (SR) of skeletal muscle contains cation-selective channels which have been detected by isotope fluxes in fragmented SR vesicles, fluorimetric dyes and direct incorporation of SR vesicles to planar phospholipid bilayers. SR channels incorporated in bilayers have a single open-state conductance of 140 pS in 0.1 MK+ (refs 4,5). We have previously reported blockade of the SR channel by Cs+, a low-affinity blocker with a zero-voltage dissociation constant of 40 mM (ref. 6). We showed that increasing Cs+ concentrations reduced the open-channel conductance, increased the mean open time and conferred voltage dependence on the open-state conductance. Here we report on the blockade induced by the cholinergic drugs decamethonium and hexamethonium on the SR channel. Although blockade by hexamethonium is similar to that of Cs+, decamethonium blocks with a much higher affinity and induces flickering events which are probably due to the interaction of single drug molecules with the open state.