BACKGROUND: Current treatment for high-grade osteosarcoma (HGO) consists in primary tumor complete surgical excision and adjuvant multi-agent combined chemotherapy for subclinical metastatic disease. In Mexico, osteosarcoma prevalence is ≤5 cases per 10,000 people; drugs targeting the disease are therefore designated orphan medicinal products. This is the case of mifamurtide, a potent monocytes and macrophages inducer. OBJECTIVES: This study aimed to determine the most cost-effective treatment for resectable, non-metastatic HGO in pediatric patients. Therapies compared were combined chemotherapy (high doses methotrexate, doxorubicin, cisplatin, with or without ifosfamide) vs combined chemotherapy plus mifamurtide.  METHODS: Efficacy data regarding combination chemotherapy alone or with mifamurtide were obtained from the INT-0133 study. A Markov model was designed using Excel™ software. According to treatment guidelines, the model considered six stages: disease-free; disease progression; recurrence; progression-free after recurrence; progression after recurrence; death. The model adopted the Mexican public health institutions’ perspective over a 60-year timeframe. Univariate sensitivity analyses were conducted to determine the robustness of the model. Average utility was calculated from published studies. Costs were from the Mexican Institute of Social Security (IMSS). Outcome measures included cost, ICER and ICUR. RESULTS: Cost-effectiveness analysis showed that while the chemotherapy combination regimen plus mifamurtide was more effective (19.74 vs. 18.17, LYG) it was also more costly (USD $102,635.8 vs. $13,148.89), with a discount rate of 3.5%. The ICER is USD $56,746.14. The cost-utility analysis found the same results, with the chemotherapy plus mifamurtide proving to be most effective treatment (19.55 vs. 17.95 QALY), or 1.60 additional QALY. The ICER was USD $55,837.7. Sensitivity analyses showed the model to be robust.  CONCLUSIONS: Mifamurtide is a cost-effective treatment for pediatric patients with osteosarcoma. The additional 1.60 QALYs are relevant for the population, offering longer survival with a better quality of life.