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IMPORTANCE:. Microvascular autoregulation (MA) maintains adequate tissue perfusion over a range of arterial blood pressure (ABP) and is frequently impaired in critical illness. MA has been studied in the brain to derive personalized hemodynamic targets after brain injury. The ability to measure MA in other organs is not known, which may inform individualized management during shock. OBJECTIVES:. This study determines the feasibility of measuring MA in skeletal muscle using near-infrared spectroscopy (NIRS) as a marker of tissue perfusion, the derivation of optimal mean arterial pressure (MAPopt), and comparison with indices from the brain. DESIGN:. Prospective observational study. SETTING:. Medical and surgical ICU in a tertiary academic hospital. PARTICIPANTS:. Adult critically ill patients requiring vasoactive support on the first day of ICU admission. MAIN OUTCOMES AND MEASURES:. Fifteen critically ill patients were enrolled. NIRS was applied simultaneously to skeletal muscle (brachioradialis) and brain (frontal cortex) while ABP was measured continuously via invasive catheter. MA correlation indices were calculated between ABP and NIRS from skeletal muscle total hemoglobin (MVx), muscle tissue saturation index (MOx), brain total hemoglobin (THx), and brain tissue saturation index (COx). Curve fitting algorithms derive the MAP with the lowest correlation index value, which is the MAPopt. RESULTS:. MAPopt values were successfully calculated for each correlation index for all patients and were frequently (77%) above 65 mm Hg. For all correlation indices, median time was substantially above impaired MA threshold (24.5–34.9%) and below target MAPopt (9.0–78.6%). Muscle and brain MAPopt show moderate correlation (MVx–THx r = 0.76, p < 0.001; MOx–COx r = 0.69, p = 0.005), with a median difference of –1.27 mm Hg (–9.85 to –0.18 mm Hg) and 0.05 mm Hg (–7.05 to 2.68 mm Hg). CONCLUSIONS AND RELEVANCE:. This study demonstrates, for the first time, the feasibility of calculating MA indices and MAPopt in skeletal muscle using NIRS. Future studies should explore the association between impaired skeletal muscle MA, ICU outcomes, and organ-specific differences in MA and MAPopt thresholds.