Intimal proliferation at the interface between prosthetic material and tissue is an intrinsic phenomenon of stenting and the major cause of insufficiency of the transjugular intrahepatic portosystemic shunt (TIPS). For its prevention, a randomized study was performed comparing standard heparin treatment with a combination of trapidil, a drug with anti–platelet-derived growth factor (PDGF) activity, and ticlopidine, a platelet aggregation inhibitor. Ninety patients with cirrhosis who received a transjugular shunt were randomized, and 84 patients completed the trial. Group 1 (n = 42) received a bolus of heparin (12 to 24 U/kg) at shunt placement, followed by 1 week of intravenous and 4 weeks of subcutaneous heparin treatment. Group 2 (n = 42) received the same heparin bolus, followed by a 1-day intravenous heparin treatment and a 6-month treatment with trapidil (400 mg/d) and ticlopidine (250 mg/d). Shunt function was assessed by duplex-sonography and angiography. Stenoses were classified according to their location as type 1 (within the stent) and type 2 (in the draining hepatic vein). The estimated rate of overall stenoses (intention-to-treat analysis) at 1 year showed a significant reduction in patients receiving trapidil and ticlopidine (group 2) as compared with heparin (33 vs. 57%; P = .047). There was no difference in the estimated 1-year rate of type 1 stenoses between the two groups, but there was a significant reduction in type 2 stenoses (group 1: 58%, group 2: 19%; P = .016). The treatment effect continued after withdrawal of the drugs and was accompanied by a decreased incidence of rebleeding. The study demonstrates that the incidence of type 2 stenosis of the transjugular shunt can be reduced by combined inhibition of platelet aggregation and PDGF activity. The findings may be of relevance not only for the transjugular shunt, but also for other stent applications, e.g., vascular and biliary, as well as for bypass and shunt surgery.