Smooth muscle cell proliferation is central to the process of restenosis. Attempts to inhibit the events leading to this proliferation have met with little success. In addition to its known antithrombotic effects, heparin also has inhibitory effects on smooth muscle cell proliferation. These effects appear to be unrelated to its anticoagulant properties and are retained in low molecular weight heparin derivatives. Although the use of heparin for as long as 18 to 24 h after coronary angioplasty in humans has not prevented restenosis, longer treatment periods have not been assessed. This study examines the effect of treatment with a low molecular weight heparin (enoxaparin) in a hypercholesterolemic rabbit iliac artery model. Control rabbits had a mean iliac artery diameter of 0.70 +/- 0.06 mm, which increased to 1.73 +/- 0.09 mm after balloon angioplasty. At follow-up angiography 4 weeks later, the mean vessel diameter was 0.56 +/- 0.12 mm. Animals treated with low dose enoxaparin (1 mg/kg per day) for 4 weeks and high dose enoxaparin (10 mg/kg per day) for either 2 or 4 weeks had similar mean luminal diameters before and immediately after angioplasty. At follow-up angiography, the mean luminal diameter was 0.82 +/- 0.17 mm for low dose enoxaparin, 1.04 +/- 0.20 mm for 2 week high dose enoxaparin (p = 0.03 versus control) and 1.19 +/- 0.09 mm for 4 week high dose enoxaparin (p = 0.001 versus control). When defined as loss of 50% of the initial gain achieved with angioplasty, restenosis was found in all control vessels.(ABSTRACT TRUNCATED AT 250 WORDS)