Tibio-peroneal trunk (TPT) lesions are usually categorized as 'complex' in anatomical classifications, which leads to the perception that endovascular therapy (EVT) will be challenging and the outcome most likely poor. This multicenter, retrospective cohort study investigates the efficacy of the EVT of TPT lesions in patients with chronic limb threatening ischemia (CLTI) or an infrapopliteal bypass at risk. The primary endpoint was limb-salvage. The secondary outcomes were technical success, freedom from clinically driven target lesion revascularization (CD-TLR), overall survival, and amputation-free survival. A total of 107 TPT lesions were treated in 101 patients. At 3 years, the limb-salvage rate was 76.4% (95% CI 66.0-86.8%). Technical success was achieved in 96.3% of cases. The freedom from CD-TLR, amputation-free survival, and overall survival at 3 years were 53.0% (95% CI 38.1-67.9%), 33.6% (95% CI 23.0-44.2%), and 47.7% (95% CI 36.1-59.3%), respectively. Reintervention significantly increased the hazard ratio for amputation by 7.65 (95% CI 2.50-23.44, p < 0.001). Our results show that the EVT of both isolated and complex TPT lesions is associated with high technical success and acceptable limb-salvage rates, with reintervention being a major risk factor for amputation. Moreover, mid-term mortality rate was relatively high. In future revisions of the anatomical grading scales, the classification of TPT lesions as highly complex should be reconsidered.