Heparin and its derivatives are known to attenuate cancer metastasis in preclinical models, but have not been used clinically due to adverse bleeding effects. This study compared the efficacy of S-NACH (a sulfated non-anticoagulant heparin) versus tinzaparin (a low molecular weight heparin) in inhibiting metastasis of a growing primary tumor and following surgical excision of primary tumor in a pancreatic cancer mouse model. The efficacy of S-NACH versus tinzaparin on metastasis of the primary tumor was evaluated in each experiment using IVIS imaging. Athymic female mice were treated with S-NACH or tinzaparin, and 30 min later luciferase-transfected pancreatic cancer cells (Mpanc96) were implanted into the spleen; treatment was continued daily until termination. Next we studied the effect of S-NACH versus tinzaparin on metastasis after surgical excision of the primary tumor after 3 weeks of daily treatment with S-NACH or tinzaparin. S-NACH reduced surgically induced metastasis (p<0.01) and tumor recurrence (p<0.05) relative to control. Histopathological studies demonstrated significant increase in tumor necrosis mediated by S-NACH and to lesser extent by tinzaparin as compared to control group. Furthermore, either S-NACH or tinzaparin upregulated the expression of the junctional adhesion molecule E-cadherin in pancreatic cancer cells where its low expression enhances cancer cell migration and invasion. In terms of bleeding time (BT), S-NACH did not affect BT as compared to tinzaparin, which doubled BT. These data suggest that S-NACH is an effective and safe anti-metastatic agent and warrants further clinical evaluation.