Objectives This study tested the effectiveness of a smoking cessation program designed for patients with peripheral artery disease (PAD). Background Tobacco use is the leading risk factor for PAD incidence and progression and for ischemic events. Tobacco cessation reduces PAD-related morbidity and mortality, yet few prospective clinical trials have evaluated smoking cessation interventions in PAD patients. Methods We recruited outpatients with lower extremity PAD identified from medical records as cigarette smokers. Participants were randomly assigned to an intensive tailored PAD-specific counseling intervention or a minimal intervention. Participants completed surveys at baseline and at 3- and 6-month follow-up. Reported 7-day point prevalent smoking abstinence was confirmed by cotinine or carbon monoxide assessment. Results In all, 687 outpatients were identified as probable smokers with lower extremity PAD; 232 met study eligibility requirements; and 124 (53% of eligible) enrolled. Participants were receptive to counselor contact: the median number of sessions was 8.5 (range 0 to 18). Participants randomly assigned to the intensive intervention group were significantly more likely to be confirmed abstinent at 6-month follow-up: 21.3% versus 6.8% in the minimal intervention group (chi-square = 5.21, p = 0.023). Conclusions Many long-term smokers with PAD are willing to initiate a serious quit attempt and to engage in an intensive smoking cessation program. Intensive intervention for tobacco dependence is a more effective smoking cessation intervention than minimal care. Studies should be conducted to examine the long-term effectiveness of intensive smoking cessation programs in this population to examine the effect of this intervention on clinical outcomes related to PAD.