In contrast to clinical trials using statin drugs, which suggest that cholesterol lowering from high to moderate levels is safe, many, but not all, prospective studies report higher nonatherosclerotic disease rates in people with low serum total cholesterol, even after deleting deaths in the 5 years after cholesterol determination. A perplexing and unanswered question is whether low cholesterol is causally related to nonatherosclerotic disease risk. Cholesterol is reduced during the acute phase reaction; a state of immune activation that persists for more than 5 years may explain the prospective observations. Higher cholesterol may be a marker for other protective substances such as fat-soluble antioxidants. Low cholesterol might mark poor nutrition, for example, during depression. Alternatively, higher cholesterol levels may result in enhanced delivery of lipids to cells during the immune response or tissue repair or may enhance defense against endotoxins and viruses. Although we believe that populationwide efforts to lower cholesterol should continue, we think that important biology may be reflected in the repeatedly observed associations of low cholesterol with nonatherosclerotic disease. The authors urge that research continue to elucidate any biologic bases of these relations.