INTRODUCTION: Individuals with Down syndrome (DS) exhibit autonomic dysfunction, which contributes to reduced work capacity. The chemically sensitive component of the exercise pressor reflex, the metaboreflex, is responsible for exercise-induced sympathoexcitation and can be assessed via post-exercise muscle ischemia (PEMI). Blunted sympathoexcitation is common in individuals with DS and contributes to the physiological basis for reduced work capacity observed this population, but the influence of the metaboreflex is unknown. Using unilateral isometric knee extension exercise with PEMI, we hypothesized that individuals with DS would demonstrate a reduced metaboreflex compared to individuals without DS. METHODS: Twenty-four individuals with DS (M/F: 13/11; 24±5yrs; 30.3±6.2kg/m2) and without DS (M/F: 13/11; 25±4yrs; 26.5±4.5kg/m2) performed a unilateral isometric knee extension at 30% of their maximal voluntary contraction using their dominant leg on a leg dynamometer. Following 2-min of contraction, a thigh-cuff was rapidly inflated to 220 mmHg on the exercised leg for 3-min to isolate the activation of the muscle metaboreflex via PEMI. Beat-to-beat systolic blood pressure (SBP), stroke volume (SV), mean arterial pressure (MAP), and cardiac output (CO) were assessed using finger photoplethysmography coupled with Modelflow. Heart rate (HR) was collected via three-lead electrocardiogram. RESULTS: Despite similar baseline values of all variables in both groups, individuals with DS demonstrated a blunted pressor response to the isometric knee extension compared to individuals without DS (SBP; DS: 133±17 vs. Non-DS: 167±28 mmHg), and the blunted SBP response was maintained with PEMI (SBP; DS: 124±19 vs. Non-DS: 150±21 mmHg; time × group interaction, p<0.001). Individuals with DS also exhibited a reduced HR 2-min into the contraction compared to those without DS (HR; DS: 90±16 vs. Non-DS: 114±22 bpm; timexgroup interaction, p<0.001). Controlling for MVC, BMI, peak torque/body weight, and quadricep fat & lean mass did not impact our results. Further, individuals with DS had a lower SV during the PEMI compared to individuals without DS (SV; DS: 93±24 vs. Non-DS: 113±23 mL/min; timexgroup interaction, p=0.003). CONCLUSION: Individuals with DS demonstrated a diminished metaboreflex response compared to their peers without DS, during a task known to induce sympathoexcitation, even when controlling for MVC. Our novel findings suggest that reduced influence of the metaboreflex contributes to the reduced exercise pressor response in persons with DS. Such exercise-specific peripheral autonomic perturbations contribute beyond our previous cardiac autonomic findings demonstrating blunted sympathoexcitatory perturbations in persons with DS, which likely contribute to reduced work capacity for this population. This research was funded in part by the American College of Sports Medicine Doctoral Research Award (#21-01558). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.