MicroRNA -17-92 (miR-17-92) cluster has been demonstrated to play a crucial role in various human cancers. However, its effects in osteosarcoma have not yet been elucidated. The purpose of this study was to investigate the clinical significance of miR-17-92 cluster in osteosarcoma. MiR-17-92 cluster expression in osteosarcoma clinical samples and cell lines was detected by real-time quantitative RT-PCR. Then, the association of miR-17-92 cluster level with survival of osteosarcoma patients was performed by the Kaplan-Meier and Cox proportional regression analyses. Furthermore, the effects of miR-17-92 cluster on tumorigenicity of osteosarcoma cell lines were evaluated by in vitro assays. The relative expression of miR-17-92 cluster in osteosarcoma tissues was significantly higher than those in adjacent normal tissues (P=0.001). And there was a relationship between miR-17-92 cluster upregulation and advanced TNM stage of osteosarcoma patients (P=0.037). Moreover, higher miR-17-92 cluster expression clearly predicted poorer Recurrence-free survival (P<0.001) and Overall survival (P=0.002). In the multivariate analysis, high miR-17-92 cluster expression was an independent prognostic factor for Recurrence-free survival (P<0.001) and Overall survival (P=0.002). Furthermore, the cellular proliferation, invasion, and migration of osteosarcoma cell lines were significantly accelerated by miR-17-92 cluster plasmid in vitro assays. Our findings showed that miR-17-92 cluster could serve as a promising marker for tumor recurrence and survival of osteosarcoma patients. Moreover, miR-17-92 cluster has been identified as a promoter for tumorigenicity of osteosarcoma cells, thus it might be a critical targeted therapy strategy for osteosarcoma.