The possible activity of ticlopidine and its analogue clopidogrel in early atherogenesis was investigated. Incubation of rabbit platelets with the extracellular matrix produced by endothelial cells in culture induced massive platelet adherence in vitro. This phenomenon was strongly reduced when platelets were isolated from rabbits that had been treated with a single dose of clopidogrel (10 mg/kg PO) or three doses of ticlopidine (each 200 mg/kg PO) (94% and 56% inhibition of platelet adhesion, respectively). Three doses of aspirin (each 200 mg/kg PO) were ineffective. Air-drying injury of the rabbit carotid artery resulted in platelet adherence to the underlying subendothelium. This platelet accumulation on the damaged vessel wall was greatly reduced by clopidogrel: 95% (p<.001) inhibition of platelet adhesion after a single oral dose of 25 mg/kg. Ticlopidine (200 mg/kg) was also effective (71% inhibition; ><.001), whereas aspirin (100 mg/kg PO) failed to reduce platelet adhesion to the subendothelium. The effect of clopidogrel on intimal smooth muscle hyperplasia in rabbit carotid arteries subjected to air-drying endothelial injury was then investigated. After a 16-day treatment, clopidogrel (25 mg/kg per day PO) inhibited the development of intimal thickening (48% inhibition;p<.01). This effect was dose dependent and increased with the duration of the treatment. Under the same experimental conditions, ticlopidine (200 mg/kg per day PO) inhibited myointimal thickening (57%;p<.001), whereas aspirin was ineffective. These results show that clopidogrel and ticlopidine, two ADP-selective antiplatelet agents, can reduce myointimal thickening after endothelial injury.