The actions of two structurally related tricyclic antidepressants on neuronal nicotinic acetylcholine receptors were investigated in human neuroblastoma (SY-SY5Y) cells, using whole-cell patch-clamp recordings. Both desipramine and imipramine reversibly inhibited inward currents evoked by application of the nicotinic receptor agonist dimethylphenylpiperazinium iodide (30–300 μM) with IC50 values of 0.17 μM and 1.0 μM respectively (holding potential −70 mV). The degree of current inhibition caused by either tricyclic compound was unaffected by agonist concentration (30–300 μM). The effects of desipramine were voltage-independent over the range −40 mV to −100 mV, and inhibition caused by imipramine only increased very slightly with membrane hyperpolarization over the same range. These results indicate that tricyclic antidepressants can inhibit neuronal nicotinic acetylcholine receptors by mechanisms which are distinct from their actions at non-neuronal nicotinic acetylcholine receptors.