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The Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) is a national medical licensing examination for physicians earning the doctor of osteopathic medicine (DO) degree. Little has been published regarding the validity of this relatively new, high-stakes examination. The purpose of this study was to examine the validity of COMLEX-USA Level 2, which is given to fourth-year osteopathic medical students and focuses on clinically relevant content. Nineteen osteopathic medical schools were asked to submit Level 2 scores and associated academic information, including predictions by deans or deans' representatives regarding whether each student would pass the examination. Twelve of the 17 schools that had students eligible to take the Level 2 examination provided data for 1254 (80%) of 1577 first-time test takers in March 2000. The overall mean score of study participants was 533.35, with a pass rate of 91.98%. The highest average correlation with COMLEX-USA Level 2 performance was with COMLEX-USA Level 1 scores (r = 0.76), followed by basic science grade point average (GPA) (r = .66), total GPA as a fourth-year student (r = .65), and clinical GPA (r = .36). Students identified as being at highest risk received the lowest mean score (427.54) and were most likely to fail Level 2. COMLEX-USA Level 2 scores are moderately to highly related to academic achievement in osteopathic medical schools.