Epidemiological studies have extensively evaluated the association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) risk. The objective of this systematic review was to enumerate the number of original prospective studies that showed a significant association between HDL-C and CVD risk and provided evidence of the consistency of this association across other lipid risk factors. A systematic MEDLINE literature search identified 53 prospective cohort and five nested case-control studies that provided multivariate assessments of the association between HDL-C and CVD risk. Among these 58 prospective studies, 31 studies found a significant inverse association between HDL-C and CVD risk for all CVD outcomes and subpopulations studied, whereas 17 studies found a significant association for some CVD outcomes and/or subpopulations assessed. The ratio of studies that found a significant association out of the total studies identified was similar across all CVD outcomes, although there was less evidence for stroke and atherosclerotic outcomes. Only seven studies tested for the consistency of this association across other lipid risk factors, of which six studies suggested that the association was consistent across other lipid levels. In conclusion, the association between HDL-C and CVD risk is significant and strong, although further evidence may be needed to establish whether this association is consistent across other lipid risk factors. Furthermore, uncertainties remain regarding the mechanism in which HDL-C exerts its effects, suggesting a need for further research focused on new methods for reliable measurement.