Correlations of atherosclerotic plaque attributes with clinical presentation have not been studied in peripheral arterial disease (PAD). The aim of the current study was to identify clinical variables associated with alterations in PAD plaque morphology. Thirty-one patients underwent intravascular ultrasonography (IVUS) at the time of arteriography for symptomatic PAD. IVUS data were analyzed with radiofrequency techniques for quantification of plaque composition, plaque volume, and total vessel volume. Associations between plaque characteristics and clinical variables were evaluated. Univariable and multivariable analyses were performed using t-test, Pearson correlations, F-tests, and analysis of variance. Calcium (Ca2+) channel blocker use was associated with a smaller total atherosclerotic plaque burden (44.2 +/- 2.7 vs 52.9 +/- 2.5%; p < .05), and decreased fibrous plaque content (18.2 +/- 1.8% vs 24.0 +/- 1.9%; p < .05). Angiotensin-converting enzyme (ACE) inhibitor use, however, was associated with a larger total atherosclerotic plaque burden (58.3 +/- 2.2% vs 42.9 +/- 2.1%; p < .01) and larger fibrous plaque content (27.2 +/- 2.0% vs 17.7 +/- 1.6%; p < .001). Multivariable analysis was performed to evaluate which factors may differentially impact the response variable measurements of plaque volume to vessel volume. Based on this model, those without the use of an antihyperlipidemic agent or ACE inhibitor had an average total atherosclerotic plaque burden of 47.7%. Those on an antihyperlipidemic agent had an average decrease of 7.0% (p < .05), whereas those on ACE inhibitors had an average increase of 16.2% from the baseline value (p < .001). The use of calcium channel blockers is associated with significantly decreased atherosclerotic plaque burden and decreased fibrous plaque content, whereas the use of ACE inhibitors was associated with an increase in plaque burden and an increased fibrous plaque content. The use of these medications in PAD may alter plaque morphology with the potential to affect clinical outcomes.