The aim of this study was to determine whether persistently high levels of interleukin-6 (IL-6) or soluble vascular adhesion molecule–1 (sVCAM-1) are associated with faster functional decline compared to fluctuating or persistently low biomarker levels in 255 participants with peripheral arterial disease. Participants underwent baseline and ≥2 annual follow-up measures of IL-6 and sVCAM-1. Participants were categorized as follows: category 1, annual levels of IL-6 (or sVCAM-1) were in the lowest tertile for ≥3 study visits; category 3, annual levels of IL-6 (or sVCAM-1) were in the highest tertile for ≥3 visits. Category 2 levels of IL-6 (or sVCAM-1) did not meet criteria for group 1 or 3. Six-minute walking distance, fastest paced 4-m walking velocity, and the Short Physical Performance Battery were measured annually. Results were adjusted for age, gender, race, co-morbidities, statin use, physical activity, the ankle-brachial index, and other confounders. Across IL-6 categories, average annual decreases in 6-minute walking distance were −21.4 feet in category 1, −49.2 feet in category 2, and −76.8 feet in category 3 (p for trend = 0.013), and average annual decreases in Short Physical Performance Battery score were −0.18, −0.45, and −0.62, respectively (p for trend = 0.022). Similar associations of IL-6 categories with decrease in fastest paced walking velocity were observed (p for trend = 0.034). There were no significant associations of sVCAM-1 categories with functional decline. In conclusion, in participants with peripheral arterial disease, persistently high IL-6 levels are associated with faster functional decline compared to those with fluctuating or persistently low IL-6 levels.