Reduced glomerular filtration rate (GFR) is associated with adverse outcomes in patients with cardiovascular disease. We explored the relationship between GFR and angiographic and clinical outcomes in ST-segment elevation myocardial infarction (STEMI) patients receiving pharamacologic reperfusion, with or without clopidogrel. Data were available to estimate GFR in 3,252 STEMI patients undergoing fibrinolysis, randomized to clopidogrel versus placebo in the CLARITY-TIMI 28 trial. Patients with a creatinine > 2.5 mg/dl were excluded from the trial. We compared outcomes between patients with no, mild or moderate reductions in baseline estimated GFR (ml/min/1.73 m²) of ≥ 90, 60-89, and <60, respectively. Compared to patients with no (n = 841) or mildly reduced GFR (n = 1897), those with moderately reduced GFR (n = 514) were older, more often female, and were more likely to have diabetes and hypertension (P ≤ 0.001 for all). The risk of the primary endpoint (an occluded infarct-related artery on angiography or death/myocardial infarction by day 8), 30 day cardiovascular events (death, myocardial infarction, or urgent revascularization for recurrent ischemia) and 30 day Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding increased as GFR declined (P for trend 0.003, <0.0001, and 0.0008 respectively). The adjusted risk of 30 day ischemic complications remained higher in patients with moderately reduced versus normal GFR (OR 1.5, 95% CI 1.0-2.1, P = 0.04). Treatment with clopidogrel tended to yield greater benefit in patients with normal or mildly reduced GFR versus in patients with moderately reduced GFR. In conclusion, STEMI patients with reduced GFR treated with medical reperfusion, including dual antiplatelet therapy, have higher rates of adverse clinical outcome. Further research on optimal STEMI therapy in this high-risk group is warranted.