Medication nonadherence is a critical problem with severe implications in individuals at risk for atherosclerotic cardiovascular disease. Many studies have attempted to predict medication adherence in this population, but few, if any, have been effective in prediction, suggesting that essential risk factors remain unidentified. This study’s objective was to (1) establish an accurate prediction model of medication adherence in individuals at risk for atherosclerotic cardiovascular disease and (2) identify significant contributing factors to the predictive accuracy of medication adherence. In particular, we aimed to use only the baseline questionnaire data to assess medication adherence prediction feasibility. A sample of 40 individuals at risk for atherosclerotic cardiovascular disease was recruited for an eight-week feasibility study. After collecting baseline data, we recorded data from a pillbox that sent events to a cloud-based server. Health measures and medication use events were analyzed using machine learning algorithms to identify variables that best predict medication adherence. Our adherence prediction model, based on only the ten most relevant variables, achieved an average error rate of 12.9%. Medication adherence was closely correlated with being encouraged to play an active role in their treatment, having confidence about what to do in an emergency, knowledge about their medications, and having a special person in their life. Our results showed the significance of clinical and psychosocial factors for predicting medication adherence in people at risk for atherosclerotic cardiovascular diseases. Clinicians and researchers can use these factors to stratify individuals to make evidence-based decisions to reduce the risks.