Current algorithms recommend computed tomography or fluoroscopic guidance rather than ultrasonography for musculoskeletal intervention. We analyzed our ultrasonographically guided experience to evaluate its efficacy. Forty-seven patients underwent needle aspirates or biopsies or both in 13 extremity and 34 axial locations for 12 inflammatory lesions, 23 soft tissue masses, and 12 lesions arising from bone. Four lesions were initially imaged by ultrasonography; the remaining lesions were identified by computed tomography (25) or magnetic resonance imaging (18). Forty-six samples were diagnostic; one needle aspirate of an inflammatory mass yielded no diagnostic material. No complications occurred. Ultrasonographically guided musculoskeletal aspiration and biopsy are diagnostic and effective throughout the body, and with appropriate lesion access, they should be considered as an alternative to computed tomographic-guided procedures.