Based on the meta-analysis and descriptive analysis of 8 studies, it was found that the MTHFR C677T mutation in osteosarcoma patients may lead to an increased risk of HD-MTX adverse reactions, such as G3-4 hepatotoxicity, G3-4 nephrotoxicity, G3-4 gastrointestinal toxicity, and G3-4 mucositis. Here, MTHFR is linked to osteosarcoma.