Introduction: Hypoglycaemia has been strongly associated with cardiovascular death in trials of intensive glycaemic control in type 2 diabetes (T2DM) patients at high cardiovascular risk for up to 90 days afterwards. Hypoglycaemia may increase cardiovascular mortality via: i) proarrhythmic effects due to abnormal cardiac repolarisation and autonomic function; and ii) prothrombotic effects via platelet hyperreactivity and altered fibrin clot properties. It was hypothesised this may be mediated by both acute and mechanisms downstream of the hypoglycaemic event and these were tested experimentally. Methods: The risk of cardiac arrhythmias was examined during spontaneous hypoglycaemia, as captured via continuous interstitial glucose and Holter monitoring in insulin-treated T2DM patients. This was complemented by hyperinsulinaemic hypoglycaemic clamp studies, where cardiovascular parameters were measured acutely and up to 7 days later in T2DM and nondiabetic subjects. Autonomic function was analysed using heart rate variability and spontaneous baroreceptor sensitivity, whilst effects on thrombosis were analysed using platelet function assays, turbidimetric and lysis assays, and scanning electron microscopy of fibrin clots. Results: During spontaneous prolonged hypoglycaemia, an 8-fold increase in bradyarrhythmias was observed. Vagal re-activation following initial transient withdrawal was observed during spontaneous as well as experimental hypoglycaemia, that only occurred in T2DM subjects. Hypoglycaemia was found to increase platelet activation and aggregation acutely, whilst also increasing fibrin clot density and depressing fibrinolysis for up to 7 days, an effect that occurred in T2DM subjects but not nondiabetic controls. Conclusions: Hypoglycaemia may override the benefits of intensive glucose control via proarrhythmic and prothrombotic mechanisms. These effects may persist beyond the acute episode and mediate short term increases in cardiovascular mortality. Hypoglycaemia should be minimised in high cardiovascular risk patients through individualised glucose lowering strategies.