OBJECTIVES: Health benefits of low-density lipoprotein cholesterol (LDL-C) at recommended levels are well known; benefits of HDL-C at recommended levels are less well documented.  This study assesses and replicates the quantification of the relationship between HDL-C and all-cause mortality while aligning relative importance to LDL-C. METHODS: A comprehensive analyses of available epidemiological studies including HDL-C and all-cause mortality as an endpoint were included in a meta-regression.  That meta-regression was independently validated with a longitudinal analysis of an Australian epidemiological database (General Practitioner Research Network) 1999-2008.  While statistical association is important, demonstration that modifications via intervention to the clinical measure (HDL-C) effect change in the endpoint is more important. RESULTS: Twenty-two epidemiological studies in 153,798 patients met the criteria. In a survival analysis for time to death, higher HDL-C is significantly associated with longer duration to death (P = 0.043); 0.33 mmol/L higher HDL and 1.33 lower total/HDL cholesterol were each associated with about a third lower vascular mortality.  Twenty-five placebo-controlled intervention trials yielded a regression that explained 83% of the variation in percent changes in cardiovascular events with parameter estimates associated with percent changes in HDL-C and LDL-C of –1.51 (P = 0.02) and 1.02 (P = 0.02).  Alternatively, a 1% increase in HDL-C equates to a 1.5% change in cardiovascular events while a 1% reduction in LDL-C equates to a 1% reduction in those events. HDL-C is statistically significantly inversely related to mortality.  Higher HDL-C is associated with a decrease in the likelihood of death (-1.73; P = 0.04) while repeated measures that are higher further decrease that probability (-<0.01: P = 0.02).  Lower LDL-C decreases the probability of death. CONCLUSIONS: The relationship between HDL-C and all-cause mortality was quantified, replicated and validated and shown to be of greater prognostic value than LDL-C.