Twist, a basic helix-loop-helix transcription factor, and E-cadherin are both correlated with the metastatic progression of several types of cancer. However, it is currently unknown whether their activations have relevance to the progression of osteosarcoma. The purpose of the present study was to investigate the clinicopathological and prognostic value of Twist and E-cadherin in osteosarcoma. Twist and E-cadherin expressions were determined by immunohistochemistry. Patient survival rates were determined by Kaplan-Meier method and log-rank test. Cox regression was adopted for multivariate analysis of prognostic factors. The positive rates of Twist and E-cadherin in 107 osteosarcoma specimens were 31.8 % (34/107) and 20.6 % (22/107), respectively. Twist expression was significantly correlated with that of E-cadherin (r = -0.209, P = 0.031). The positive expression of Twist and E-cadherin was significantly associated with metastasis in 107 osteosarcoma specimens (both P < 0.05). Patients with positive Twist expression had significantly poorer overall survival (OS; P < 0.05) and disease-free survival (DFS, P < 0.05) when compared with patients with the negative expression of Twist. Patients with positive expression of E-cadherin had significantly poorer OS (P < 0.05) when compared with patients with negative E-cadherin expression, but not a significantly poorer DFS (P = 0.081). On multivariate analysis, Twist expression and age were found to be independent prognostic factors for OS (both P < 0.05) and DFS (both P < 0.05). Our results suggest that Twist was expressed significantly more and E-cadherin significantly less in osteosarcoma with metastasis, and expression of both might be related to the prediction of metastasis potency and poor prognosis for patients with osteosarcoma.