Background Hyaluronic acid fillers are the second-most commonly performed nonsurgical procedure. Arterial thrombosis is their most devastating complication. Recent research shows that along hyaluronic acid thrombi, a platelet/fibrin thrombus forms in the site of injection. This is not addressed by current management protocols, which focus on perivascular hyaluronidase plus adjuvant strategies to increase blood flow. We experimented with an animal model utilizing both hyaluronidase and a thrombolytic agent for treatment of occlusion. Objectives The authors sought to evaluate the efficacy of a combined treatment of hyaluronidase with a thrombolytic agent applied perivascularly to an artery occluded with hyaluronic acid. Methods After direct intravascular injection into the femoral artery, rats were randomized to receive one of the following perivascular solutions: saline, hyaluronidase, alteplase, or hyaluronidase + alteplase. Reperfusion, distal bleeding, and microscopic findings were evaluated 4 hours after intervention. Results None of the subjects in the control group showed signs of reperfusion. In the hyaluronidase group, 60% reperfused, 10% completely, the rest only partially. In the alteplase group, 50% reperfused partially. In the hyaluronidase + alteplase group, 50% had partial and 50% complete prepermeabilization. Kruskal-Wallis test showed a P < 0.0001 favoring hyaluronidase + alteplase. Microscopic findings were compatible with bleeding rates. Conclusions Both hyaluronic acid and red thrombi play a role in the occluded vessel. Perivascular application of hyaluronidase with a thrombolytic agent seems to achieve greater reperfusion rates than either one alone. If proven safe in humans, this strategy could make treatment more effective while still being suitable for an outpatient setting.