OBJECTIVES Type I Gaucher's disease (GD) and Fabry's disease (FD) are rare genetic disorders which in their severest form cause great disability or may be life threatening. Treatment for these conditions includes costly enzyme replacement therapy (ERT) with uncertain evidence of effectiveness. With increasing frequency ERT has been financed with National Health Insurance funds in response to court rulings. This study seeks to estimate the economic burden of GD and FD for Colombian society. METHODS We developed a stochastic, discrete event simulation model of the natural history of these diseases with and without ERT and their respective direct and indirect costs during a 15 year period (2008-2022) for a hypothetic cohort of patients. Model parameters were obtained from secondary data from local and international sources, expert opinion and administrative cost databases from a national health insurance plan. One-way sensitivity analyses included scenarios with different population disease prevalence and ERT dosage. RESULTS In the best scenarios the 15-year total cost of the cohort is between USD$319 and 533 million for GD and between US$84 and 92 million for FD. Costs of ERT represent more than 95% of total cost. For the year 2008 the annual cost of ERT per patient for either disease was around US$175,000. CONCLUSIONS A decision to finance ERT for these diseases with public funds would require an amount of resources that exceeds by far the available budget and would imply not providing treatment for other diseases. Given that a recent Constitutional Court ruling mandates reforms to the Colombian benefits packages and their rationing mechanisms, our results highlight the importance of economic evaluation for sound decision making. Development and enforcement of national treatment guidelines for rare diseases is needed. Financing policies should be coherent with the objective of providing comprehensive and effective services within health sector budget constraints.