Background: The effectiveness of second-line palliative chemotherapy in patients with recurrent/metastatic osteosarcoma is not well defined. Several small studies (6–19 patients) have reported on ifosfamide as second-line treatment. In this study we report our single-center experience with second-line ifosfamide monotherapy in patients treated for recurrent/metastatic osteosarcoma. Methods: A chart review was conducted of all patients with osteosarcoma treated with ifosfamide from 1978 until 2017. Until 1997 a 5 g/m2 regimen was used, and from 1997 onwards a 9 g/m2 regimen was used. Overall survival (OS) from start of ifosfamide was the primary endpoint. Progression-free survival (PFS) from start of treatment was also studied. To assess difference in survival between groups the log rank test was applied. To investigate the effect of ifosfamide dose and World Health Organization performance status (PS) a Cox proportional hazard regression model was estimated. Results: Sixty-two patients were selected with recurrent/metastatic osteosarcoma treated with second-line ifosfamide monotherapy (dose of 5 g/m2, n = 26; 9 g/m2, n = 36). OS was significantly better in univariate analysis for 9 g/m2 compared with 5 g/m2 (10.9 months [95% confidence interval (CI), 9.3–12.6] vs. 6.7 months [95% CI, 5.9–7.6], respectively) and for PS (median OS PS 0, 13.0 months [95% CI, 2.3–23.8]; PS 1, 8.2 months [95% CI, 5.4–11.1]; PS ≥2, 6.2 months [95% CI, 2.2–10.3]; and unknown PS, 5.4 months [95% CI, 2.2–8.5]). In multivariate analysis only PS showed a significant difference. No difference in PFS was found between 5 and 9 g/m2 ifosfamide treatment or PS. Conclusion: This study suggests that ifosfamide is an effective second-line treatment for patients with recurrent/metastatic osteosarcoma. Implications for Practice: Ifosfamide monotherapy is commonly used as second-line treatment in osteosarcoma, although large series to support this are lacking. This retrospective study reports overall and progression-free survival for regimens with 5 g/m2 and with 9 g/m2. This study was unable to show a significant difference in survival between 5 and 9 g/m2 but showed an important impact of World Health Organization performance status on overall survival. This study sets a standard and reference for comparison with the multiple phase II studies under development.