Purpose: Osteosarcoma is the most common primary malignancy of bone with a dismal prognosis for patients with pulmonary metastases. Evaluation of osteosarcoma prognosis would facilitate the prognosis consultation as well as the development of personalized treatment decisions. However, there is limited effective prognostic predictor at present. Lung Immune Prognostic Index (LIPI) is a novel prognostic factor in pulmonary cancers, whereas, the prognostic significance of LIPI in osteosarcoma has not yet been well clarified. In this study, we firstly explore the prognostic role of LIPI and further modify this predictive model in osteosarcoma. Patients and methods: A retrospectively study was conducted at Musculoskeletal Tumor Center of West China Hospital between January 2016 and January 2021. Hematological factors and clinical features of osteosarcoma patients were collected and analyzed. The area under curve (AUC) and optimal cuff-off of each single hematological factor was calculated. Results: In this study, lactate dehydrogenase (LDH), derived neurtrophil to lymphocyte ratio (dNLR), and Hydroxybutyrate dehydrogenase (HBDH) have higher AUC values. LIPI was composed of LDH and dNLR and was further modified by combing the HBDH, forming the osteosarcoma immune prognostic index (OIPI). OIPI divided 223 osteosarcoma patients divided into four groups, none, light, moderate, and severe (p < 0.0001). OIPI has a higher AUC value than LIPI and other hematological indexes in t-ROC curve. According to the univariate and multivariate analysis, pathological fracture, metastasis, NLR, platelet-lymphocyte ratio (PLR), and OIPI were associated with the prognosis; and metastasis and OIPI were independent prognostic factors of osteosarcoma patients. An OIPI-based nomogram was also established and could predict the 3-year and 5-year overall survival. In addition, OIPI was also revealed correlated with metastasis and pathological fracture in osteosarcoma. Conclusion: This study first explore the prognostic significance of LIPI in osteosarcoma patients. In addition, we developed a modified LIPI, the OIPI, for osteosarcoma patients. Both the LIPI and OIPI could predict the overall survival of osteosarcoma patients well, while OIPI may be more suitable for osteosarcoma patients. In particular, OIPI may have the ability to identify some high-risk patients from clinically low-risk patients.Copyright © 2022 He, Tang, Zou, Li, Wang, Kenmegne, Zhou, Lu, Min, Luo and Tu.