Based on a systematic review of over 20 cohort studies, a clear association exists, for both men and women, between particularly low cholesterol levels and the rate of non-coronary mortality. The excess in women appears mainly confined to non-cancer causes, particularly respiratory and digestive diseases, while there is also an excess of deaths from cancer seen in men with low cholesterol levels. Higher mortality rates from trauma, haemorrhagic stroke and cirrhosis have also been observed. Much of this association is known to be as a consequence of the disease with a fall in cholesterol levels seen after developing a variety of inflammatory diseases. However, the excess risk of non-coronary heart disease deaths is still apparent by excluding deaths within five years suggesting that effect-cause is not the only explanation. Confounding still remains the most likely explanation for the association with an underlying chronic disease or risk factor causing both the low cholesterol and the fatal event. However, there is still the possibility that some of the increased risk is due to the low cholesterol. This makes it important that appropriately controlled trials of both drug and dietary interventions demonstrate net clinical benefit among those with low levels of coronary risk before cholesterol-lowering strategies are adopted more widely in these groups.