BACKGROUND: Post-myocardial infarction ventricular septal defect (VSD) complicates approximately 2% of myocardial infarctions. Thrombolytic therapy may accelerate the time from myocardial infarction to VSD formation. The effects of thrombolytic therapy in patients with a post-myocardial infarction VSD were investigated. METHOD: Demographic, procedural, and event data were retrospectively analysed in patients transferred to a regional cardiothoracic centre with the diagnosis of post-myocardial infarction VSD over five years. RESULTS: Twenty nine patients were analysed; 15 received thrombolytic therapy: 10 (<12 hours) early and five (> or =12 hours) late. The median time to post-myocardial infarction VSD was shorter with thrombolytic therapy at 1 v 5.5 days (p=0.01). The median time to post-myocardial infarction VSD was shorter with early compared with late thrombolytic therapy at 1 v 6 days (p<0.01). There was no difference between late and no thrombolytic therapy, 5.5 v 6 days. Patients treated with thrombolytic therapy had a trend towards higher mortality at 11/15 (73%) compared with 5/14 (36%) (p=0.066). Twenty five (86%) patients had surgery. All four not having surgery died. Surgical survival was 13/25 (52%) at discharge and six months of follow up. Within the surgical group survival with prior thrombolytic therapy was 4/25 (25%) and 9/13 (69%) without (p=0.07). CONCLUSION: There appears to be an earlier presentation of post-myocardial infarction VSD when thrombolytic therapy has been used. An early presentation can carry a worse prognosis and may have implications for the identification and treatment of this life threatening complication.