Although statins lower serum cholesterol by inhibiting hepatic HMG coenzyme A reductase (HMG-CoA), this mechanism cannot explain recent observations that these drugs are immunomodulatory^1,2. Cholesterol is an essential component of plasma membrane sphingolipid rafts and its depletion by agents such as methylβcyclodextrin (MβCD) disrupts rafts and prevents intracellular signalling by immune receptors such as the IgE receptor, FcεRI³. As cellular HMG-CoA is required for the de novo synthesis of plasma membrane cholesterol⁴, we investigated the effect of statins on allergen-induced mast cell activation. Using the model cell line, RBL-2H3, we demonstrate that 48 h pre-treatment with either fluvastatin or lovastatin can completely inhibit FcεRI-mediated cellular degranulation. Dose-response experiments suggest these compounds are active at nanomolar concentrations (IC₅₀ for fluvastatin and lovastatin of 0.5 and 29 nM, respectively). Cuvette fluorimetry of fura 2-loaded cells reveal that both fluvastatin and lovastatin pre-treatment (at 3 μM) inhibit allergen-induced calcium responses by 42 and 39%, respectively. These effects of statins were similar to those seen by physical depletion of plasma membrane cholesterol using MβCD (10 mM). The observed effects of statins are due to inhibition of HMG-CoA since they are reversed by co-incubation with mevalonic acid. Visualisation of lipid rafts using fluorescent cholera toxin B revealed that statins inhibit receptor-triggered raft aggregation equivalent to that observed following cholesterol depletion by MβCD. Furthermore statin treatment of human bone marrow-derived mast cells similarly inhibits degranulation and calcium signalling. Taken together, these data suggest that statins may uncouple FcεRI signal transduction by disrupting lipid raft function through inhibition of plasma membrane cholesterol signalling. Statins may, therefore, offer a novel therapeutic approach to the treatment of allergy.