Background: Retrospective studies have suggested the potential of apatinib, an anti-angiogenesis tyrosine kinase inhibitor, plus ifosfamide and etoposide (IE) over IE in advanced osteosarcoma. This trial aimed to further compared apatinib plus IE versus IE alone in patients with advanced osteosarcomas post first-line chemotherapy failure. Methods: In this multicenter, randomized controlled trial, patients with histologically confirmed osteosarcoma, progressing after at least one prior line of chemotherapy, were randomized (2:1) to either apatinib plus IE or IE alone. The apatinib plus IE group received oral apatinib 500mg daily plus ifosfamide (1.8 g/m²/d) and etoposide (100 mg/m²/d) on days 1-3, every 3 weeks. The IE group received IE on days 1-5, every 3 weeks. Apatinib was continued until disease progression or for a maximum of one year, and IE was administered for up to 10 cycles. The primary endpoint was progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1. Results: A total of 81 patients were enrolled, with 53 receiving apatinib and IE, while 28 using IE alone. The median follow-up period was 9.5 (interquartile range, 7.1 to 13.0) months. The apatinib plus IE group showed a median PFS of 5.5 months (95% confidence interval [CI], 3.9 to 6.7), compared to 3.4 months (95% CI, 1.4 to 4.6) in the IE group, yielding a hazard ratio of 0.41 (95% CI, 0.24 to 0.71), P=0.0010. Objective response rates were 32.1% (95% CI, 19.9 to 46.3) for the apatinib plus IE group and 25.0% (95% CI, 10.7 to 44.9) for the IE group. Disease control rates were numerically higher in the apatinib plus IE group at 90.6% (95% CI, 79.3 to 96.9), compared to 60.7% (95% CI, 40.6 to 78.5) in the IE group. The median time to response was 1.4 months (95% CI, 1.2 to 2.6) for the apatinib plus IE group and 1.5 months (95% CI, 1.3 to 2.0) for the IE group. Duration of response also favored the apatinib plus IE group, with a median of 6.1 months (95% CI, 1.9 to 8.0) compared to 4.1 months (95% CI, 1.7 to not estimated [NE]) in the IE group. The median overall survival has not yet been reached in either group. Grade 3-4 treatment-related adverse events occurred in 69.8% of patients in the apatinib plus IE group and 64.3% in the IE group, with the most common events being white blood cell count decreased and neutrophil count decreased. Conclusions: Apatinib plus IE demonstrated a significant improvement in PFS in patients with advanced osteosarcomas, with an acceptable safety. Clinical trial information: NCT05277480.