Because clinical skills play an important role in health services, many medical credentialing organizations are making performance-based assessments part of the board-certification and licensure processes. While clinical skills are taught and evaluated at colleges of osteopathic medicine, the development and validation of standardized assessment methodologies is far from complete. The purpose of this study was to gather data to support the use of a performance-based assessment of osteopathic clinical skills. A sample of 121 fourth-year osteopathic medical students was tested using the Comprehensive Osteopathic Medical Licensing Examination-USA performance-based clinical skills examination (COMLEX-USA-PE) prototype, a standardized patient performance evaluation that involves a series of 12 simulated encounters. Students were evaluated in a number of domains that included history taking, physical examination, osteopathic manipulative treatment techniques, written communication and clinical problem solving, and physician-patient communication. The analysis of data from 1452 standardized patient encounters suggests that reliable and valid scores can be obtained using the current prototype. The use of COMLEX-USA-PE to assess the readiness of osteopathic medical students to provide patient care in supervised graduate medical education training programs is supported.