We retrospectively collected the clinical data and follow-up information of patients with osteosarcoma who were admitted to Department of Orthopedics, RenMin Hospital of Wuhan University from January 2010 to December 2016 and explore the relationship between red cell distribution width (RDW) and prognosis of patients with osteosarcoma. The present study finally included 271 patients with osteosarcoma with median follow-up time of 24.2 months (3–69 months). According to the RDW median, 135 patients belong to the low RDW group and 136 patients belong to high RDW group. Compared with low RDW group, the high RDW group tend to have metastasis (50 vs 32.6%, P=0.004), higher poor response rate to chemotherapy compared with the low RDW group (24.3 vs 7.4%, P=0.000) and higher C-reactive protein (CRP) (7.6 ± 4.9 vs 5.5 ± 4.5, t = 3.727, P=0.000). There was slightly significant difference in the types of pathology (χ2 = 8.059, P=0.045). The Kaplan–Meier analysis indicated survival curve of high RDW group was poorer than that in the low RDW group (P=0.020). The univariate cox analysis indicated that patients with RDW ≥ median had higher risk of poor prognosis compared with those who had RDW level < median (HR = 2.41, 95% confidence interval (CI): 1.51–3.83, P=0.000). After adjusting some potential cofounding factors, the elevated RDW was still associated with poor prognosis (HR = 1.66, 95% CI: 1.07–2.56, P=0.024). The elevated pretreatment RDW was associated with poor overall survival (OS) in patients with osteosarcoma and can be an independent predictor of prognosis.