The tetracyclines are antimicrobials that also inhibit expression of certain matrix metalloproteinases (MMPs). We conducted a series of experiments to determine if minocycline could inhibit MMP expression and limit human aortic smooth muscle cell (SMC) proliferation and migration. Analysis of SMC proliferation was performed after cells were grown in minocycline-incubated media. SMC migration activity was assayed in a micro-Boyden chamber. Western blotting revealed that minocycline reduced SMC production of MMP-2 in a dose dependent manner. Increasing doses of minocycline progressively reduced SMC proliferation to 49% of control values and limited SMC migration to 15% of control. When administered to rats with balloon injured carotid arteries, intraperitoneal doses of minocycline (70-100 mg/kg) reduced neointima formation by 76%, but were associated with liver toxicity. Higher doses were lethal and lower doses were ineffective. Minocycline, applied to injured arteries in a pluronic gel with a low pH, was also ineffective. In summary, minocycline lowers MMP-2 expression, reduces SMC proliferation and migration, and inhibits neointimal hyperplasia, but its efficacy is limited by systemic toxicity.