Background: Portable ultrasound machines are now common, used for point-of-care applications and needle guidance for percutaneous procedures; however, the effectiveness of portable ultrasound in evaluation of the musculoskeletal system has not been fully assessed. Purpose: To prospectively evaluate the use of portable hand-held ultrasound in comparison with conventional cart-based ultrasound in evaluation of the musculoskeletal system. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: In this institutional review board–approved, prospective study, 100 consecutive patients with informed consent were imaged through use of both portable and cart-based ultrasound equipment using 12-5 MHz linear transducers. Agreement in ultrasound diagnosis was documented along with expected clinical changes in management if there was disagreement (definitely no, probably no, uncertain, probably yes, definitely yes). Imaging details of disagreement cases were recorded, and descriptive statistics were calculated. Results: There were 42 male and 58 female patients (mean ± SD age, 53 ± 13 years) imaged over a time period of 20 months. Anatomic areas scanned were the shoulder (n = 30), elbow (n = 11), hand and wrist (n = 15), hip (n = 10), knee (n = 11), foot and ankle (n = 12), and others (n = 11). Scanning with conventional ultrasound revealed abnormality in 92% of patients. Agreement in diagnosis made between portable versus cart-based ultrasound was found in 65% of patients. In the 35% of patients with discordant results, the change in diagnosis resulted in no change in clinical management in 46%, probably no change in 29%, uncertain change in 14%, probable change in 11%, and definite change in 0%. The diagnoses changing management (4%; 4/100) included nondetection of a satellite nodule (n = 1), ganglion cyst (n = 1), hernia (n = 1), and underestimated tendon tear (n = 1). Conclusion: When compared with conventional cart-based ultrasound, a musculoskeletal diagnosis using portable hand-held ultrasound was concordant or was discordant without clinical relevance in 96% (96/100) of patients. Knowledge of benefits and limitations of portable hand-held ultrasound will help determine areas where specific types of ultrasound equipment can be used.