The objective of this study is to evaluate retrospectively the effectiveness of multiple-drug chemotherapeutics regimen that included high-dose methotrexate (HD-MTX) for treating primary osteosarcoma. 148 newly diagnosed patients with Stage I and II osteosarcoma who received HD-MTX/HD-MTX/DDP(cisplatin)/ADM(doxorubicin) and/or HD-MTX/IFO(Ifosfamide)/DDP/ADM before and after the surgery were retrospectively analyzed to measure the efficacy of this regimen. The significance of various variables as predictive prognostic factors of the patient survival rate was also evaluated. The overall 3-year survival rate of the patients was 79.73 %. The survival rate was improved to 85.71 % in the patients who received surgery and a complete 4-cycle chemotherapy. In addition, the rates of disease-free survival (DFS), local recurrence, and distant metastasis were 68.13, 3.30, and 10.81 %, respectively. Our analysis showed that completing 4-cycle chemotherapy produced a significant impact on the overall 3-year survival and DFS rates (P < 0.05). The overall 3-year survival was correlated with pathological fracture, chemotherapy completion, histological response, local recurrence, and distance metastasis (single-factor P < 0.05). Multivariate analysis further evidenced that these predictive factors were independently correlated to the survival rate (multi-factor P < 0.05). The complete 4-cycle multiple-drug chemotherapy consisting of HD-MTX, doxorubicin, cisplatin, and ifosfamide combined with surgical resection was found to be effective in improving the survival rate of osteosarcoma patients. Furthermore, the presence of pathological fracture, poor histological response, local recurrence, and distant metastasis was negatively correlated with the survival rate. Patient age, gender, location of primary tumor, and serum alkaline phosphatase level were not found to show the prognostic significance.