OBJECTIVES: Methylmalonic academia (MMA) and propionic academia (PA) are rare inborn errors of metabolism that cause significant morbidity and are associated with early mortality among patients. The mainstay of the long-term medical management relies on a lifelong protein-restricted and high-energy diet. Liver transplantation is a relatively infrequently used alternative therapy that corrects the metabolic errors and potentially improves survival and quality of life. The objective of this study is to estimate the incremental clinical and economic outcomes associated with liver transplantation vs. nutritional support among patients with MMA and PA. METHODS: We constructed a three health state Markov model using data derived from the United Network for Organ Sharing (UNOS) database, meta-analyses, cohort studies, narrative reviews, and expert opinions when necessary. Societal and payer perspectives were considered. Lifetime direct and indirect costs, life expectancies, and quality-adjusted life-years (QALYs) were estimated based on one-year model cycles for hypothetical cohorts of newborns with MMA and PA, respectively. We conducted a series of one-way sensitivity analyses to assess the impact of parameter assumptions on the result. Scenario analyses were performed, including a worst-case scenario setting all parameters to favor nutritional support. RESULTS: In the base case analysis liver transplantation was the dominant strategy, saving $1,594,995 in lifetime societal costs and generating 8 more QALYs compared to nutritional support. Liver transplantation remained dominant from the payer perspective, saving  $1,171,978 throughout lifetime. In one-way sensitivity analyses we found that discount rate and annual mortality rates are the most influential parameters on costs and QALYs respectively. In the worse-case scenario, liver transplantation still produced lower costs but lower QALYs (-12.1) compared to the nutritional support group. CONCLUSIONS: Liver transplantation appears to be a cost-effective treatment alternative compared to nutritional support in MMA and PA patients. Future research is needed on the long-term survival and quality of life in these patient populations.