Background: The comparative clinical effectiveness of new (reteplase, tenecteplase) vs. older (alteplase, streptokinase) thrombolytic agents in the treatment of acute myocardial infarction is uncertain. Aim: To examine 30–35 day mortality and major adverse effects of thrombolytic agents in the treatment of acute myocardial infarction. Design: Systematic review of randomized controlled trials comparing the clinical efficacy of included drug regimens. Methods: We searched MEDLINE, EMBASE, Science Citation Index/Web of Science from 1980 to December 2001, and the Cochrane Library (2001, Issue 4). Reference lists of included studies and a number of medical journals were hand searched. Randomized controlled trials that compared any two of the included drugs provided to patients in the early stages of acute myocardial infarction, were included. Outcome measures included: mortality, bleeding, stroke, reinfarction, allergy and anaphylaxis. Results: We found 14 studies, total study population 142 907. For available comparisons (all alteplase vs. streptokinase, reteplase vs. streptokinase or alteplase, tenecteplase vs. alteplase), meta‐analysis showed no significant differences in mortality at 30–35 days. The GUSTO‐I study showed an apparent benefit of accelerated alteplase over streptokinase, but its inclusion or exclusion made little difference. Total stroke and haemorrhagic stroke rates were lower for streptokinase than for all alteplase combined (total stroke, OR 1.29, 95%CI 1.13–1.46; haemorrhagic stroke OR 1.83, 95%CI 1.14–2.93). Discussion: All thrombolytic drugs appear to be of similar efficacy in reducing mortality, and the apparent benefits of accelerated alteplase in GUSTO‐I are consistent with this. Whether accelerated alteplase is sufficiently different from other regimens of administering alteplase to be excluded from a meta‐analysis, and whether more weight should be placed on a meta‐analysis than on a single trial, are matters for debate.