Antipsychotic drugs are known to cause a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be due to impaired islet cell function. We have studied the effects of the atypical antipsychotic clozapine and of the conventional drug haloperidol on electrical and secretory activity in rat pancreatic beta-cells. Islets of Langerhans were isolated from adult Sprague-Dawley rats (killed humanely) by collagenase digestion and dispersed into single cells by brief incubation in a calcium-free medium. Electrical activity and total K⁺ conductance were recorded using the perforated patch technique (Best et al. 2004) and single K⁺ channel activity in cell-attached patches (Sheader et al. 2001). Insulin release was measured by radioimmunoassay using intact islets (Best et al. 2004). In the presence of 4 mM glucose, 5 μM clozapine had little or no effect on membrane potential, but hyperpolarised the cell membrane potential in the presence of 16 mM glucose, resulting in a complete inhibition of electrical activity. In contrast, 5 μM haloperidol caused a marked depolarisation of the membrane potential in the presence of low or high concentrations of glucose. In the presence of 10 mM glucose, clozapine increased beta-cell input conductance from 0.59 ± 0.09 to 1.13 ± 0.17 nS (both n=11, p<0.01 by paired t test). In contrast, haloperidol reduced input conductance in the absence of glucose from 3.48 ± 0.81 to 1.62 ± 0.20 nS (n=5, p<0.05 by paired t test). Cell-attached recordings indicated that these effects were due, at least in part, to changes in K_ATP channel activity. Thus, in the presence of 2 mM glucose, channel open probability was increased by clozapine from 0.43 ± 0.06 (n=8) to 0.59 ± 0.06 (n=4, p<0.01 by paired t test) and reduced by haloperidol to 0.04 ± 0.04 (n=4, p<0.001 by paired t test). In the presence of 4 mM glucose, neither drug significantly affected insulin release. In the presence of 16 mM glucose, secretion was increased 7.5-fold. Under such conditions, clozapine significantly (p<0.05) inhibited insulin release by approximately 40%, whereas haloperidol had no significant effect. We conclude that clozapine and haloperidol exert contrasting actions on electrical activity in rat pancreatic beta-cells as a result of opposing effects on K⁺ permeability.