Purpose: To investigate the levels of systemic heparanase, inflammatory markers, and coagulation factor activities in patients with retinal vein occlusion (RVO). Methods: This prospective study included 18 patients with central RVO, 22 patients with branch RVO, and 40 patients with age-related cataract as the control group. Serum heparanase protein levels and activities were measured by ELISA and a heparan degrading enzyme assay kit, respectively. Serum levels of MMP-2, MMP-9, TLR-2, and TLR-4 were measured by ELISA kits. The activities of coagulation factors (V, VII, VIII, and IX) were determined with an autoanalyzer. The Mann–Whitney U test was used to compare the above parameters between patients with RVO and control subjects. The relationship between two of the above parameters was analyzed by Spearman's correlation. Results: Patients with RVO had higher levels of systemic heparanase protein, heparanase activities, coagulation factors' (V, VIII, and IX) activities, MMP-2, MMP-9, TLR-2, and TLR-4 compared with the control group. Systemic heparanase levels were correlated with serum levels of MMP-2, MMP-9, TLR-2, TLR-4, and activities of coagulation factors VIII and IX. Conclusion: Increase of systemic heparanase in RVO is associated with activation of systemic inflammation and blood hypercoagulability.