Introduction: Intensive care unit acquired weakness (ICU-AW) results from a complex mixture of nerve and muscle pathology, and early identification is challenging. This pilot study was designed to examine the ultrasonographic changes that occur in muscles during ICU hospitalization. Methods: Patients admitted to the ICU for acute respiratory failure were enrolled prospectively and underwent serial muscle ultrasound for thickness and gray-scale assessment of the tibialis anterior, rectus femoris, abductor digiti minimi, biceps, and diaphragm muscles over 14 days. Results: Sixteen participants were enrolled. The tibialis anterior (P = 0.001) and rectus femoris (P = 0.041) had significant decreases in gray-scale standard deviation when analyzed over 14 days. No muscles showed significant changes in thickness. Conclusions: Ultrasound is an informative technique for assessing muscles of patients in the ICU, and lower extremity muscles demonstrated increased homogeneity during ICU stays. This technique should be examined further for diagnosing and tracking those with ICU-AW. © 2012 Wiley Periodicals, Inc.