Peripheral arterial disease (PAD) is associated with an increased risk of early death in cardiovascular (CV) disease. The majority of PAD subjects are asymptomatic with a prevalence of 11 per cent among the elderly. Long-term drug prevention aiming to minimize disease progression and CV events in these subjects is probably beneficial, but expensive. The purpose of this analysis was to evaluate the cost-effectiveness of pharmacological risk reduction in subclinical PAD. Long-term costs and quality-adjusted life years (QALYs) were estimated by employing a decision-analytic model for ACE-inhibitor, statin, aspirin and non-aspirin anti-platelet therapy. Rates of CV events without treatment were derived from epidemiological studies and event rate reduction were retrieved from clinical trials. Costs and health-related quality of life estimates were obtained from published sources. All four drugs reduced CV events. Using ACE-inhibition resulted in a heart rate (HR) of 0.67 (95% CI: 0.55-0.79), statins 0.74 (0.70-0.79), and clopidogrel 0.72 (0.43-1.00). Aspirin had a HR of 0.87 and the 95% CI passed included one (0.72-1.03). ACE-inhibition was associated with the largest reduction in events leading to the highest gain in QALYs (7.95). Furthermore, ACE-inhibitors were associated with the lowest mean cost €40.556. In conclusion, while all drugs reduced CV events, ACE-inhibition was the most cost-effective. These results suggest that we should consider efforts to identify patients with asymptomatic PAD and, when identified, offer ACE-inhibition.