Abstract Aims Thrombolysis is an alternative to surgery for mechanical prosthetic valve thrombosis (MPVT). Randomized clinical trials have yet to test the safety and efficacy of a proposed ultraslow thrombolytic infusion regimen. Methods and results This single-centre, open-label, pilot randomized clinical trial randomized adult patients with acute obstructive MPVT to an ultraslow thrombolytic regimen [25 mg of recombinant tissue-type plasminogen activator (rtPA) infused in 25 h] and a fast thrombolytic regimen (50 mg of rtPA infused in 6 h). If thrombolysis failed, a repeated dose of 25 mg of rtPA for 6 h was administered in both groups up to a cumulative dose of 150 mg or the occurrence of a complication. The primary outcome was a complete MPVT resolution (>75% fall in the obstructive gradient by transthoracic echocardiography, <10° limitation in opening and closing valve motion angles by fluoroscopy, and symptom improvement). The key safety outcome was a Bleeding Academic Research Consortium type III or V major bleeding. Overall, 120 patients, including 63 (52.5%) women, at a mean age of 36.3 ± 15.3 years, were randomized. Complete thrombolysis success was achieved in 51 patients (85.0%) in the ultraslow-regimen group and 47 patients (78.3%) in the fast-regimen group [odds ratio 1.58; 95% confidence interval (CI) 0.25–1.63; P = 0.34]. One case of transient ischaemic attack and three cases of intracranial haemorrhage (absolute risk difference −6.6%; 95%CI −12% −0.3%; P = 0.07) were observed only in the fast-regimen group. Conclusion The ultraslow thrombolytic regimen conferred a high thrombosis resolution rate without major complications. Such findings should be replicated in more adequately powered trials.