Background: High coronary thrombus burden has been associated with unfavorable outcomes in patients with ST-segment elevation myocardial infarction (STEMI), the optimal management of which has not yet to be established. Methods: We evaluated the safety and efficacy of adjunctive catheter-directed thrombolysis (CDT) during primary percutaneous coronary intervention (PCI) in patients with STEMI and high thrombus burden. Results: Among the 1,849 consecutive patients with STEMI, 263 had high thrombus burden. Moreover, 41 patients received intracoronary infusion of tissue plasminogen activator during primary PCI (CDT group), whereas 222 did not receive (non-CDT group). No significant differences in bleeding complications and in-hospital and long-term mortalities were observed (9.8% vs. 7.2%, p=0.53; 7.3% vs. 2.3%, p=0.11; and 12.6% vs. 17.5%, p=0.84, CDT vs. non-CDT). In patients who underwent antecedent aspiration thrombectomy during PCI (75.6%; CDT group and 87.4%; non-CDT group), thrombolysis in myocardial infarction grade 2 or 3 flow rate after thrombectomy was significantly lower in the CDT group than in the non-CDT group (32.2% vs. 61.0%, p<0.01). However, the final rates improved considerably without significant difference (90.3% vs. 97.4%, p=0.14). Conclusions: For STEMI patients with high thrombus burden, adjunctive CDT is safe and effective for improving coronary flow. CDT resulted in favorable coronary flow even after unsatisfactory aspiration thrombectomy.