Background: Sirolimus-coated balloons (SCBs) have emerged as a promising alternative to paclitaxel-coated devices for the treatment of femoropopliteal lesions. However, real-world data on SCB performance in also complex peripheral arterial disease remains unknown. We sought to evaluate the safety and 12-month clinical outcomes of the Selution SLR™ balloon angioplasty in a challenging real-world patient cohort. Methods: This single-center, retrospective observational study with prospective follow-up included 21 patients with symptomatic peripheral arterial disease treated with the Selution SLR™ SCB (Med. Alliance, SA, Mont-sur-Rolle, Switzerland) after vessel preparation with rotational atherectomy, between October 2023 and November 2024. The primary endpoints were technical success, 12-month primary patency, and target lesion revascularization (TLR). Secondary endpoints included major adverse cardiac events (MACE), major adverse limb events (MALE), and changes in Rutherford classification and ankle-brachial index (ABI). Results: The median age was 79 years, with 47.6% of patients over 80 years old. Most patients presented with advanced peripheral atherosclerotic disease (PAD) (Rutherford category V, 47.6%). Lesions were predominantly occlusive (76.2%), with a median length of 130 mm and severe/moderate calcified in 71.4% of cases. Technical success was achieved in 95.2% of procedures. The 12-month primary patency was 95%, with a TLR-Rate of 5%. No major amputations or cardiovascular deaths occurred. Significant improvements in Rutherford category and ABI were maintained at 12 months. Conclusions: In this real-world cohort of patients with complex PAD, vessel preparation-assisted Selution SLR™ angioplasty demonstrated safety and promising 12-month outcomes. These findings support the use of SCBs in also challenging peripheral interventions, though larger-scale data and further follow up are needed in order to establish SCBs’ role as crucial in the treatment algorithm of PAD.