BACKGROUND: r-tPA (recombinant tissue-type plasminogen activator) and its variant, TNK (tenecteplase), are the currently approved thrombolytic drugs for the treatment of acute ischemic stroke, but they are ineffective in a proportion of patients due to r-tPA resistance of platelet-rich thrombi. A novel thrombolytic, caADAMTS13 (constitutively active a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) has been shown to improve experimental stroke outcomes where platelet-rich thrombi are present but have not been directly compared with r-tPA or TNK. METHODS: We conducted a direct comparison of caADAMTS13 versus r-tPA versus TNK versus vehicle control in the ferric chloride–mediated distal middle cerebral artery occlusion model in mice, which features platelet and VWF (von Willebrand Factor)–rich thrombi that reproduce r-tPA-resistant occlusion. Treatments were administered intravenously 1 hour after ferric chloride application by bolus injection or bolus followed by infusion, as translationally applicable. Laser speckle contrast imaging measured early reperfusion over the hour following treatment, and magnetic resonance imaging measured cerebral blood flow and lesion volume at 24 hours. RESULTS: Reperfusion 1 hour after treatment was greatest in caADAMTS13-treated animals. Later cerebral blood flow, 24 hours post-treatment, within the stroke-affected hypoperfused area was higher in caADAMTS13 and r-tPA but not TNK-treated mice. Functionally, this led to the absence of an initial behavioral deficit in caADAMTS13-treated mice, alongside a smaller lesion volume at 24 hours and reduced extent of bleeding. CONCLUSIONS: These findings demonstrate an overall suggestion that caADAMTS13 has improved thrombolytic efficacy, compared with current stroke treatments, against platelet-rich thrombi, for which there is currently an unmet clinical need.