OBJECTIVES:  Public health burdens of rare diseases are usually unknown due to small patient numbers and limited outcomes data. We aimed to quantify mortality gaps in HoFH, a rare genetic disorder characterised by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels and premature mortality from accelerated atherosclerosis. A modelling approach was employed to estimate the expected reductions in cardiovascular (CV) events and mortality, resulting from treatment with lomitapide as an adjunct to standard of care in patients with HoFH. METHODS:  Age-dependent hazards and treatment-dependent hazard ratios (HRs) for mortality and time to first major CV event (MACE) were calculated from survival curves for a cohort of 113 South African HoFH patients. CV-related mortality hazards were calculated by adjusting for general population non-CV-related mortality. The HR reported in the South African data was a 0.77 per mmol/L reduction in LDL-C for mortality and a 0.84 per mmol/L reduction in LDL-C for MACE. These HRs and a 38% average reduction in LDL-C with lomitapide treatment were used to adjust CV-related hazards and construct survival curves for lomitapide-treated patients (after combining the reduced CV-related hazards with non-CV-related hazards in the case of mortality). RESULTS:  Baseline median survival with current treatments (LDL-C = 8.7 mmol/L) was 48 years. The survival benefit analysis suggested that lifetime lomitapide treatment would increase median patient life expectancy by 11.7 years and median time to first MACE by 6.7 years. When treatment was initiated in adult HoFH patients (starting age 18 years), median predicted gains were 11.2 years for life expectancy and 5.7 years for time to first MACE. Achieving a LDL-C goal of a 3.3 mmol/L reduction from baseline is expected to increase survival by 12 years. CONCLUSIONS:  Modelling analyses suggest HoFH burden remains high. Further studies are warranted to determine CV morbidity and mortality benefits of lipid-lowering therapies.