The epidemiology of maintenance dialysis patients and heart failure patients has striking similarities. Both groups have a high prevalence of comorbid conditions, a high hospitalization rate, a low self-reported quality of life, and an excessively high mortality risk, mostly because of cardiovascular causes. Observational studies in both dialysis and heart failure patients have indicated the lack of a significant association between the traditional cardiovascular risk factors and mortality, or the existence of a paradoxic or reverse association, in that obesity, hypercholesterolemia, and hypertension appear to confer survival advantages. The time discrepancy between the 2 sets of risk factors, that is, overnutrition (long-term killer) versus undernutrition (short-term killer) may explain the overwhelming role of malnutrition, inflammation, and cachexia in causing the reverse epidemiology, which may exist in more than 20 million Americans. We have reviewed the opposing views about the concept of reverse epidemiology in dialysis and heart failure patients, the recent Die Deutsche Diabetes Dialyze study findings, and the possible role of racial disparities. Contradictory findings on hyperhomocysteinemia in dialysis patients are reviewed in greater details as a possible example of publication bias. Additional findings related to intravenous iron and serum ferritin, calcium, and leptin levels in dialysis patients may enhance our understanding of the new paradigm. The association between obesity and increased death risk in kidney transplanted patients is reviewed as an example of the reversal of reverse epidemiology. Studying the epidemiology of dialysis patients as the archetypical population with such paradoxic associations may lead to the development of population-specific guidelines and treatment strategies beyond the current Framingham cardiovascular risk factor paradigm.