Serious bleeding and embolic events are common after fibrinolytic therapy (FT) for left-sided prosthetic valve thrombosis (PVT), and are believed to occur more frequently with prolonged fibrinolytic infusions. But there is no data from prospective studies examining this contention. Our aim was to determine the timing of adverse events after FT with streptokinase (SK) for left-sided PVT. In a post-hoc analysis involving all 120 participants from a randomized controlled trial of FT for left-sided PVT, we determined the timing of occurrence of a composite of death, major bleeding, embolic stroke, or non-central nervous system systemic embolism, in relation to the duration of SK infusion. The composite outcome occurred in 20 (16.7%) of the 120 patients. Adverse events were more frequent within 12 h of initiating treatment than later (28% vs. 10%; OR 3.75, 95% CI 1.25-11.20, P = 0.018). Contrary to current thinking, adverse events can occur early during fibrinolytic therapy for left-sided PVT. This has important implications for the use of fibrinolysis as first line treatment for left-sided PVT.