Optimal management of prosthetic heart valve obstruction (PHVO) remains controversial even though surgery is usually recommended. To better define the efficacy and safety of fibrinolysis versus surgery in the pre- and post-transoesophageal echocardiography (TEE) eras. We analysed initial results and follow-up data from a large, retrospective, single-centre series, comparing fibrinolysis and surgery in patients with PHVO treated over 20 years. Two hundred and sixty-three consecutive episodes of PHVO in 210 patients, mainly left sided, were managed in our institution by either fibrinolysis (n=127) or surgery (n=136). Early clinical evolution was assessed in terms of haemodynamic success and complications. Concerning early results, there were no significant differences between the two groups in terms of mortality (10%). However, haemodynamic success was significantly more frequent in the surgical group (89% versus 70.9% p<0.001), embolic episodes were significantly more frequent in the fibrinolysis group (15% versus 0.7%, p<0.001), as were total complications (25.2% versus 11.1%, p=0.005). Long-term follow-up, with a mean duration of 6 years (range: 0-20), was obtained and showed significantly better results in the surgical group in terms of recurrence (p=0.021) and mortality (p=0.002). In univariate and multivariable analyses, NYHA functional class at presentation was a strong predictor of late death (p<0.01). Management of patients during the pre- and post-TEE eras was significantly different, since introduction of TEE surgery has become the preferred therapeutic strategy. Results of this extensive single-centre experience indicate that since the introduction of TEE, surgery is more frequently performed than fibrinolysis due to the improvement of thromboembolic risk assessment. Furthermore, prompt surgical treatment is associated with a better early success rate and a significantly lower incidence of complications than fibrinolysis in left-sided PHVO. However, fibrinolysis may be justified in selected cases. Long-term follow-up showed significantly better results in the surgical group in terms of recurrence and mortality.