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Background: Doxorubicin, cisplatin, and high‐dose methotrexate (HDMTX) are the backbone of pediatric osteosarcoma treatment. However, due to toxicity concerns and the lack of data regarding efficacy in adults, high‐dose methotrexate is rarely used in the adult population. Methods: This single‐center retrospective study examined 33 patients who received HDMTX (12 g/m2, maximum 20 g) for the treatment of osteosarcoma at Oregon Health and Science University (OHSU) from 2011 to 2017. Time to serum methotrexate level ≤0.1 µmol/L was the primary outcome. Secondary outcomes included number of HDMTX doses received, methotrexate‐related toxicities, and disease outcomes including histologic response at resection and metastasis‐free survival. Results: Median age was 20 years [range 7‐38]; 14 patients ≤18 years old and 19 patients >18 years old. Median time to clearance for patients ≤18 years was 79 hours (range 63‐116) compared to 120 hours (range 77‐315) for patients >18 years (P < 0.001). No correlation between age and histologic response at resection was observed (P = 0.50), but there was a significant positive correlation between the number of HDMTX doses received before resection and histologic response (r = 0.49, P = 0.006). There was no significant difference in metastasis‐free survival between age groups, although a trend toward improved survival was noted for patients who received at least seven doses of HDMTX. Conclusion: Age over 18 years correlates with delayed methotrexate clearance and fewer administered doses of methotrexate, without increased toxicity. The potential benefit of HDMTX in young adults with osteosarcoma may outweigh toxicity risks. Young adults take longer to clear methotrexate and receive fewer cycles of HDMTX compared to adolescents, but do not experience increased toxicity. Patients who receive more cycles of HDMTX may have better outcomes, regardless of age. [ABSTRACT FROM AUTHOR]