Hypercholesterolemia has been implicated as a risk factor for atherosclerosis by numerous observational studies in the general population. Observational studies in patients suffering from various chronic illnesses and in individuals with advanced age have indicated an inverse association between cholesterol level and mortality, suggesting that the classical Framingham paradigm may not apply to these groups. It is yet unclear what the reasons for these paradoxically inverse associations are. We present a summary of the descriptive studies that have examined the association between cholesterol levels and outcomes in a variety of patient groups. The various possible mechanisms behind the observed “lipid paradox” and the potential implications of reverse epidemiology of hypercholesterolemia in clinical medicine and public health are discussed.