Background To improve their standing in residency selection, many osteopathic medical students choose to take the United States Medical Licensing Examination (USMLE). Although scores on USMLE Step 1 and Level 1 of the Comprehensive Osteopathic Medical Licensing Examination (COMLEX-USA) are known to be highly correlated, scarce data exist on the association between COMLEX-USA Level 2-Cognitive Evaluation (CE) and USMLE Step 2 Clinical Knowledge (CK) scores. In this study, we aimed to determine the association between COMLEX-USA Level 2-CE and USMLE Step 2 CK scores and derive an equation to predict performance on USMLE Step 2 CK for applicants who have only taken COMLEX-USA. Methodology We reviewed COMLEX-USA Level 2-CE and USMLE Step 2 CK scores for all students at the Lake Erie College of Osteopathic Medicine from May 2020 to April 2021. Linear regression was used to evaluate the relationship between COMLEX-USA Level 2-CE and USMLE Step 2 CK scores. Results A total of 340 students took both COMLEX-USA Level 2-CE and USMLE Step 2 CK. There was a linear association between COMLEX-USA Level 2-CE and USMLE Step 2 CK scores such that every one-point increase in COMLEX-USA was associated with a 0.13-point increase in USMLE Step 2 CK score (standard error = 9.1; model R = 0.64). Conclusions Students or programs interested in predicting performance on USMLE Step 2 CK from performance on COMLEX-USA Level 2-CE can do so using the following equation: USMLE Step 2 CK = 0.13(COMLEX-USA Level 2-CE) + 163.5.