1. Pharmacological blockade of the Human ether-a-go-go related gene (HERG) potassium channel is commonly linked with acquired long QT syndrome and associated proarrhythmia. The objectives of this study were (i) to identify and characterise any inhibitory action on HERG of the selective-serotonin re-uptake inhibitor fluvoxamine, (ii) to then determine whether fluvoxamine shared the consensus molecular determinants of HERG blockade of those drugs so far tested. 2. Heterologous HERG potassium current (I(HERG)) was measured at 37 degrees C, using the whole-cell patch-clamp technique, from a mammalian cell line (Human embryonic kidney 293) expressing HERG channels. I(HERG) tails, following repolarisation from +20 to -40 mV, were blocked by fluvoxamine with an IC(50) of 3.8 micro M. 3. Blockade of wild-type HERG was of extremely rapid onset (within 10 ms) and showed voltage dependence, with fluvoxamine also inducing a leftward shift in voltage-dependent activation of I(HERG). Characteristics of block were consistent with a component of closed channel (or extremely rapidly developing open channel) blockade and dependence on open and inactivated channel states. The attenuated-inactivation mutation S631A partially reduced the blocking effect of fluvoxamine. 4. The S6 mutations, Y652A and F656A, and the pore helix mutant S631A only partially attenuated blockade by fluvoxamine at concentrations causing profound blockade of wild-type HERG. 5. All HERG-blocking pharmaceuticals studied to date have been shown to block F656 mutant channels with over 100-fold reduced potency compared to their blockade of the wild-type channel. Fluvoxamine is therefore quite distinct in this regard from previously studied agents.