Background: Statin-associated muscle symptoms are one of the side effects that physicians should consider when prescribing statins. In this study, creatine kinase (CK) levels were measured following statin prescription, and various factors affecting the CK levels were determined using machine learning.Methods: Changes in the CK were observed every 3 months for a 12-month period in patients who received statins for the first time at Seoul St. Mary's Hospital. For each visit, we developed four basic models based on changes in the CK levels. Extreme gradient boosting, a scalable end-to-end tree boosting algorithm, which employs a decision-tree-based ensemble machine learning algorithm, was used for the prediction of changes in the CK.Results: A total of 23,860 patients were included. Among them, 19 patients (0.08%) had increased CK levels of 2,000 IU·L⁻¹ or more 3 months after statin prescription, and 65 patients (0.27%) exhibited CK levels of over 2,000 IU·L⁻¹ at least once during the 12-month study period. The area under the receiver operator characteristic of each model for each visit was 0.709–0.769, and the accuracy was 0.700–0.803. In each of the models, the variables that had the strongest influence on changes in the CK were sex and previous CK value.Conclusions: Through machine learning, factors influencing changes in the CK were identified. These results will provide the basis for future research, through which the optimal parameters of the CK prediction model can be found and the model can be used in clinical applications.