Acute promyelocytic leukaemia (APL) confers an increased risk of thrombosis and bleeding. Current treatments are insufficient to inhibit these complications. We recently showed that a combined immunoinhibitory and immunostimulatory short interference (si) RNA effectively inhibited leukaemic growth and metastasis in rats with APL. We now asked if the reported anti-leukaemic effects of siRNA treatment could be explained by inhibition of hypercoagulability. We measured markers of coagulation and fibrinolysis in plasma collected from APL rats with overt leukaemia using conventional assays. Coagulopathy developed in untreated leukaemic rats evidenced by increase in several haemostatic markers. Treatment of leukaemic rats with the siRNA reduced (p < 0.05) the concentration of thrombin-anti-thrombin complex (a marker of coagulation) by 40% compared with rats treated with an inactive, control siRNA. Substantial reductions (p < 0.05) were also obtained for two markers of fibrinolysis: D-dimer (72%) and plasminogen activator inhibitor type 1 (51%). The activity of tissue factor, the main initiator of coagulation, was not increased (p > 0.05) in untreated leukaemic rats compared with healthy rats, and did not change (p > 0.05) upon treatment with the siRNA. The bifunctional siRNA reduces the hypercoagulable state in APL in addition to its direct anti-leukaemic properties, supporting testing of this small molecule in human APL.