Background: Tumor necrosis rate after neoadjuvant therapy is one of the strongest predictors of long-term outcome for patients with osteosarcoma. Patients with good response (tumor necrosis rate ≥90%) have a substantially better survival than those with poor response (tumor necrosis rate < 90%), with 5-year overall survival of 75-80% and 55-65%, respectively. However, treatments for osteosarcoma have not yet shown much progress since the introduction of perioperative chemotherapy in 1970s. New neoadjuvant combinations are required to explored for osteosarcoma. Methods: In this phase II trial (NCT04294511), patients aged 14-65 years with histopathologically confirmed osteosarcoma and Eastern Cooperative Oncology Group performance status of 0-1 received three 21-day cycles of neoadjuvant regimen (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m² or liposomal doxorubicin 25 mg/m² on days 1-2 of cycles 1 and 3; cisplatin 100 mg/m² on day 2 of cycles 1 and 3; methotrexate 8-12 g/m² on day 12 of cycle 1; and ifosfamide 3 g/m² on days 1-4 of cycle 2). Surgery was scheduled 12-14 days after neoadjuvant therapy. Two weeks after surgery, patients received 6 cycles of adjuvant therapy (camrelizumab 200 mg on day 1 of each cycle; doxorubicin 37.5 mg/m² or liposomal doxorubicin 25 mg/m² on days 9-10 of cycles 1, 3, and 5; cisplatin 100 mg/m² on day 10 of cycles 1, 3, and 5; methotrexate 8-12 g/m² on day 2 of cycles 1, 3, and 5; and ifosfamide 3 g/m² on days 1-4 of cycles 2, 4, and 6). The primary endpoint was good response (tumor necrosis rate ≥90%) rate after neoadjuvant therapy. Results: A total of 86 patients were screened and 75 patients signed informed consent from December 2019 to June 2022. By the data cutoff date on December, 2022, 8 patients did not complete neoadjuvant therapy and 2 patients refused surgery. 65 patients completed neoadjuvant therapy, one patient had disease progression before surgery, 64 received surgical resection and adjuvant therapy, and 44 completed adjuvant therapy. Thirty-one (48.4%, 95%CI: 36.6%-60.4%) of 64 patients showed good response. The most common grade 3-4 adverse events were decreased platelet count (44.0%), decreased white blood cell (37.3%), decreased neutrophil count (29.3%), oral mucositis (14.7%), increased alanine aminotransferase (12.0%), and increased aspartate aminotransferase (10.7%). Conclusions: Camrelizumab combined with doxorubicin, cisplatin, methotrexate and ifosfamide in the perioperative treatment of osteosarcoma patients were safe and tolerable. Postoperative good response rate was similar to previously reported results. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of patients with osteosarcoma. Clinical trial information: NCT04294511.