In the setting of ST-segment elevation myocardial infarction (STEMI), the Thrombolysis In Myocardial Infarction (TIMI) risk score (TRS) and indexes of epicardial and myocardial perfusion are associated with mortality. The association between TRS at presentation and angiographic indexes of epicardial and myocardial perfusion after reperfusion therapy has not been investigated. We hypothesized that TRS, TIMI flow grade (TFG), and TIMI myocardial perfusion grade (TMPG) would provide independent prognostic information and that angiographic indexes of poor flow and perfusion would be associated with a higher TRS. TRS and angiographic data were evaluated in 3,801 patients from the TIMI 4, 10A, 10B, 14, 20, 23, and 24 trials. Within each TRS stratum (TRS 0 to 2, 3 to 4, >/=5), 30-day mortality increased stepwise among patients with impaired TFG at 60 minutes after fibrinolytic administration. In a multivariate model adjusting for the TRS strata, impaired TMPG (0/1) was independently associated with higher mortality (odds ratio 2.28, p = 0.018). In a multivariate model adjusting for the TFG and infarct location, the likelihood of impaired TMPG (0/1) was greater among intermediate-risk (TRS 3 to 4) and high-risk (TRS >/=5) patients than among low-risk (TRS 0 to 2) patients (odds ratio 1.43, p = 0.019 and 1.50, p = 0.055, respectively). Thus, impaired epicardial flow and myocardial perfusion are independently associated with increased 30-day mortality among patients identified by TRS as high risk, although there is no synergism between either TFG or TMPG and TRS. High TRS at presentation is associated with abnormal myocardial perfusion, even after adjusting for possible confounders.