Objective This study compared oxygen uptake before and after the onset of claudication in individuals with peripheral artery disease (PAD) during a 6-minute walk test, and identified predictors of the change in oxygen uptake after the onset of claudication pain. Methods The study included 50 individuals with PAD. During a 6-minute walk test, 33 experienced claudication (pain group), and 17 were pain-free (pain-free group). Oxygen uptake and ambulatory cadence were the primary outcomes evaluated during the 6-minute walk test. Results The pain group experienced onset of claudication pain at a mean (standard deviation) of 179 (45) meters and continued to walk to achieve a 6-minute walk distance of 393 (74) meters, which was similar to the 401 (76) meters walked in the pain-free group ( P = .74). Oxygen uptake increased ( P < .0001) after the onset of pain in the pain group, and this change was greater ( P = .025) than the increase in oxygen uptake from the second to fifth minutes of walking in the pain-free group. Ambulatory cadence decreased after the onset of pain in the pain group ( P = .0003). The change in oxygen uptake was associated with metabolic syndrome ( P = .0023), 6-minute walk distance ( P = .0037), age ( P = .0041), and oxygen uptake during the second minute of the test ( P = .012). Conclusion Claudication increases oxygen uptake of self-paced, over-the-ground ambulation, despite a decrease in cadence. The pain-mediated increase in oxygen uptake was blunted in individuals with metabolic syndrome, suggesting that the ability to increase oxygen uptake during ambulation is impaired. The clinical significance is that claudication increases the metabolic cost of ambulation, thereby increasing the relative intensity of exercise and reducing the tolerance to sustain ambulation.