The PREDIMED (PREvención con DIeta MEDiterránea) is a multicentre trial analyzed as a prospective cohort study. A total of 7122 participants (aged 55–80 years) at high risk of cardiovascular disease in the PREDIMED trial were recruited in 11 centres in Spain. The prevalence of subjects with type 2 diabetes was 50%. Our objective was to determine the contribution of lifestyle factors to the development of peripheral artery disease (PAD). Incident clinical PAD in relation to a healthy lifestyle 5-point score defined as adherence to a Mediterranean diet (MedDiet), moderate alcohol intake, regular physical activity, normal weight (BMI<25) and non-smoking was measured. Eighty-seven incident PAD cases were diagnosed during a median follow-up of 4.8 years. Compared with participants with 0 or 1 healthy lifestyle factor, the multivariable hazard ratio for PAD was 0.65 (95% confidence interval (CI) 0.37 to 1.14) for 2 factors, and 0.40 (0.22–0.72) for 3 or more. Moderate alcohol consumption, non-smoking, physical activity and following a MedDiet were significantly inversely associated with PAD whereas no association was found for normal weight (BMI<25 kg/m2). PAD risk monotonically decreased with an increasing number of lifestyle factors, and the greatest reduction was found for a score combining moderate alcohol consumption, MedDiet and physical activity or non-smoking. The multivariable-adjusted population attributable risk percent for the combination of these 4 factors was 80.5% (95% CI: 21.3%–95.1%). Our results demonstrate that a simple healthy lifestyle score is associated with a substantially reduced risk of PAD in a high cardiovascular risk population with a high prevalence (50%) of subjects with type 2 diabetes. •An increasing healthy lifestyle score was associated with a decreasing risk of PAD.•Factors include non-smoking, physical activity, MedDiet and moderate alcohol use.•Around 80% of new cases of PAD might have been prevented.•Our finding should be included in health promotion messages to the general public.