PURPOSE: Long-term outcomes of paclitaxel-coated drug-coated balloons (DCBs) in patients with diabetes mellitus (DM) and infrainguinal peripheral arterial disease (PAD) are incompletely defined. In the current study, we evaluated 5-year outcomes in the diabetic cohort of BIOLUX P-III. PATIENTS AND METHODS: BIOLUX P-III was a prospective, international, multicenter, post-market, single-arm study evaluating the Passeo-18 Lux DCB in routine practice. Between October 2014 and January 2017, 877 patients with infrainguinal lesions were treated at 47 centers, of whom 418 (47.7%) had DM. The primary clinical endpoint was 6-month freedom from major adverse events (MAEs), defined as freedom from procedure- or device-related death through 30 days, major target-limb amputation, or clinically driven target-lesion revascularization (CD-TLR). The primary performance endpoint was 12-month freedom from CD-TLR. Time-to-event outcomes were analyzed using Kaplan-Meier methods and the Log rank test. RESULTS: Among 877 treated patients, 418 had DM. Follow-up completion was 81.6%, 86.4%, 82.3%, and 31.3% at 6, 12, 24, and 60 months, respectively. At 5 years, freedom from MAE was lower in patients with DM than in those without DM (71.2% vs 74.7%; P = 0.0359), whereas freedom from CD-TLR was similar between groups (79.8% vs 79.6%; P = 0.535). Patients with DM also had lower overall survival (56.3% vs 73.8%; P < 0.0001), lower freedom from major target-limb amputation (92.4% vs 98.8%; P < 0.0001), and lower amputation-free survival (53.0% vs 73.6%; P < 0.0001). CONCLUSION: In this real-world registry, the Passeo-18 Lux DCB was associated with durable freedom from reintervention through 5 years, with similar CD-TLR rates in patients with and without DM. Patients with DM had poorer long-term survival and limb outcomes. However, these findings should be interpreted in the context of baseline between-group differences and limited 60-month follow-up (ClinicalTrials.gov number, NCT02276313). Peripheral arterial disease is a condition in which the blood vessels supplying the legs become narrowed or blocked. This can reduce blood flow, cause pain when walking, delay wound healing, and in severe cases increase the risk of amputation. People with diabetes are at especially high risk because they often have more severe artery disease and more other health problems that affect the heart, kidneys, and circulation. This study examined the long-term outcomes of a treatment called the Passeo-18 Lux drug-coated balloon in patients with leg artery disease. A drug-coated balloon is used during angioplasty to open narrowed arteries and deliver a medicine called paclitaxel to the artery wall to help reduce re-narrowing. We analyzed 877 patients treated in routine clinical practice, including 418 patients with diabetes, and followed outcomes for up to 5 years. We found that the need for repeat treatment of the same artery was similar in patients with and without diabetes. This suggests that the device performed well at the level of the treated artery over the long term. However, patients with diabetes had worse overall outcomes, including lower survival, higher rates of major amputation, and lower amputation-free survival. These findings suggest that, although the drug-coated balloon may provide durable treatment of the target lesion, long-term outcomes in patients with diabetes are also strongly influenced by the severity of their underlying disease and by other medical conditions. The results highlight the importance of not only restoring blood flow, but also providing ongoing wound care, diabetes management, cardiovascular risk reduction, and close multidisciplinary follow-up. The study has limitations. It was an observational registry rather than a randomized trial, the analyses were not adjusted for all baseline differences between groups, and follow-up was incomplete at 5 years. For these reasons, the findings should be interpreted with caution.