Acute lower limb ischemia (ALI) is a sudden decrease in arterial limb perfusion due to an arterial blockage, threatening limb and life. Catheter-directed thrombolysis (CDT) is a minimally invasive procedure to remove such obstructions. However, approximately one-third of patients endure a re-occlusion after successful CDT. This study aimed to investigate the short- and long-term outcomes of CDT for early (<1 year) and late (>1 year) re-occlusions. This retrospective multicenter study reviewed patients from 2 medical centers with an acute arterial re-occlusion of the lower limb after successful CDT between December 1996 and April 2021. The primary endpoints were angiographic success, defined as thrombus dissolution over 95% with outflow to at least 1 crural artery, and clinical success, defined as a score of ≥1 on the Rutherford scale for assessing changes in clinical status. Secondary endpoints included bleeding complications, patency, amputation, and mortality. Kaplan-Meier analyses were used to estimate patency, survival, and freedom from amputation. Seventy-seven cases were included, with 52 early re-occlusions (<1 year) and 25 late re-occlusions (>1 year). The median time to re-occlusion since the last CDT treatment was 4 months in the early re-occlusion group and 24 months in the late re-occlusion group. Angiographic success was achieved in 73% of early and 64% of late re-occlusions. Clinical success rates were 80.8% for the early and 80.0% of the late re-occlusion cases. Major bleeding occurred in 2% of the early and 8% of the late re-occlusion group. Patients were followed up until symptoms or signs of limb ischemia were resolved, with a median follow-up time of 15 months for the early and 22 months for the late re-occlusion group. During follow-up, secondary re-occlusions were observed in 59.6% of the early and 44% in the late group. Cumulative amputation rates at 1, 5, and 8 years were 36%, 36%, and 52% for early and 18%, 30%, and 30% for the late re-occlusions, respectively. In our experience, CDT is an effective short-term revascularization strategy for the majority of patients with both early and late re-occlusions. Long-term results are limited by secondary re-occlusions and limb loss. Catheter-directed thrombolysis (CDT) is a well-established treatment for acute lower limb ischemia (ALI). Re-occlusions after successful treatment are, however, observed in almost a third of the patients. Yet, the outcomes of CDT for re-occlusions for patients who were previously treated with CDT are not well known. This study showed that CDT is effective in achieving revascularization in cases of early and late re-occlusion after treatment for ALI, but the risk for further re-occlusions is high. Future studies should focus on maintaining patency after successful CDT for ALI.