Background Fewer than half of individuals with peripheral artery disease (PAD) experience classic claudication, and the relationships between PAD typical or atypical symptom intensity, location, and description (classic or atypical) with ischemic changes have not previously been reported. Objective The primary purpose of this study was to evaluate the relationship between self-reported PAD symptom intensity and calf tissue ischemia measured using the tissue saturation index (TSI) during treadmill exercise. The location and descriptors of atypical PAD symptoms in the presence of calf tissue ischemia were also identified. Methods Adults with PAD with exercise-limiting ischemic symptoms were asked to (a) rate symptom intensity using a numerical rating scale (NRS) from 0 to 5 (0 = no pain, 1 = onset of pain, 5 = maximal pain), (b) provide symptom locations and descriptors, and (c) wear a near-infrared spectroscopy device to obtain calf TSI values during treadmill exercise. Multilevel models with TSI as the outcome variable were estimated during exercise and recovery. Covariates included were exercise time, recovery time, baseline TSI, exercise rating, recovery rating, ankle-brachial index (ABI), age, race, gender, body mass index, diabetes, neuropathy, and smoking. Results During three successive bouts of treadmill exercise for 40 participants (80% Caucasian men; average age = 68 years, SD = 9.2), the most rapid decline in TSI occurred between the start of exercise and symptom onset (when NRS = 1). The TSI nadir was often reached prior to report of maximum discomfort (when NRS = 5), and changes in TSI were related to exercise time (p <.001), baseline TSI (p <.001), exercise ratings (p <.001), and ABI (p <.05). During recovery, TSI increased steadily for most participants as pain eased. In the recovery model, changes in TSI were associated with recovery ratings (p <.001) and ABI (p <.03). Of 120 treadmill exercise tests, 69.2% were stopped due to discomfort in the calf with classic descriptors reported only half the time (55.4%). Discussion Exploratory analyses revealed ischemic symptoms extended beyond classic claudication locations and descriptors. Future research should evaluate changes in TSI relative to atypical locations and descriptors to improve understanding of the full range of ischemic symptoms experienced by individuals with PAD.