Purpose: To evaluate the use of drug-coated balloons in a real-world patient population with peripheral arterial disease and analyse the impact of sex on mid-term outcomes following their utilisation. Methods: The BIOLUX P-III is a prospective, international, multi-centre, registry of patients with infra-inguinal lesions treated using the Passeo-18 Lux, a drug-coated balloon. Our study is a 24-month subgroup analysis of these patients; primary endpoints were freedom from major adverse events and clinically driven target lesion re-vascularisation within 12 months post-intervention. Results: Of the 877 patients in the registry, 561 (64.0%) were male and 316 (36.0%) were female. Chronic limb threatening ischaemia (Rutherford class ≥ 4) occurred in 35.7% of males and 40.6% of females. Rates of freedom from major adverse events and clinically driven target lesion re-vascularisation at 12 months were 87.3% (95% confidence interval [CI] 84.2–89.9) and 90.4% (95% CI 86.5–93.3), and 92.3% (95% CI 89.9–94.1) and 92.9% (95% CI 89.7–95.1) in males and females, respectively. All-cause mortality at 24 months was 12.0% (95% CI 9.4–15.3) in males and 11.9% (95% CI 8.6–16.5) in females. The major target limb amputation rate at 24 months was 9.1% (95% CI 6.9–11.9) in males and 4.0% (95% CI 2.3–7.0) in females. Conclusion: Treatment with the Passeo-18 Lux DCB demonstrated high efficacy and low complication rates. Despite the greater proportion of chronic limb threatening ischaemia observed in females, males were at a greater risk of ipsilateral major limb amputation and major adverse events following drug-coated balloon utilisation. Clinical Trial Registration: NCT02276313. Level of Evidence: Level 4.