Glucocorticoid receptor DNA binding factor 1 (GRF-1) is an important Rho family GTPase-activating protein, and the dysregulation of GRF-1 expression maybe involved in tumor progression. However, the role of GRF-1 expression in the osteosarcoma prognosis has been well less elaborated. Here, we conducted a hospital-based case study, including 247 patients with pathologically confirmed osteosarcoma to evaluate the associations between GRF-1 expression and osteosarcoma prognosis. We found that high GRF-1 expression was correlated with poor outcome of osteosarcoma compared with low GRF-1 expression (the median recurrence-free survival times, 11 months vs 56 months; the median overall survival times, 18 months vs 53 months). Like tumor stage, the GRF-1 expression was an independent prognostic factor influencing the survival of osteosarcoma [hazard ratio values (95 % confidence interval) were 5.39 (3.54-8.20) for recurrence-free survival (RFS) and 6.58 (4.44-9.74) for overall survival (OS), respectively]. Furthermore, the high expression of GRF-1 was significantly associated with larger tumor size, tumor dedifferentiation, and increasing metastasis risk. Functionally, the knockdown of GRF-1 expression inhibited tumor cells proliferation and induced cell apoptosis. These results indicate for the first time that GRF-1 expression may modify osteosarcoma prognosis and may be a potential tumor therapeutic target.