Background: The characteristics and survival in patients with malignant giant tumor cancer of bone (GCTB) have not been investigated thoroughly due to the limited population. We evaluated the issues based on a large cohort in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients who were diagnosed with malignant GCTB from 1975 to 2016 were extracted from the SEER database. The overall survival (OS) was calculated by Kaplan–Meier analysis and the inter-group difference was tested by log-rank test. Univariate and multivariate Cox proportional hazard regression were conducted to identify the independent survival factors. Results: A total of 325 patients with malignant GCTB were included. The overall 1-, 5-, and 10-year survival rates were 94.3% (95% CI: 91.7-96.8), 82.3% (95% CI: 77.9-86.6), and 80.1% (95% CI: 75.4-84.7), respectively. In the univariate analysis, age older than 34 years, grade IV, T2/3 stage, M1, distant and surgery of the primary site were independent factors for worse survival. Multivariate Cox regression showed the poor survival in patients with age older than 34 years (hazard ratio (HR) =3.65, 95% CI: 2.04-6.56, P <0.001), T2 stage (HR=4.85, 95% CI: 1.52-15.47, P =0.008), and distant tumor (HR=2.93, 95% CI: 1.24-6.88, P =0.014), and the extra-skeletal sites (HR=8.84, 95% CI: 2.89-27.07, P <0.001), respectively. Conclusions: This large population-based series described the clinical characteristics of the malignant GCTB. Age >34 years, T2, distant stage and extra-skeletal sites were associated with worse survival in the patients with malignant GCTB.