Background: Hospitalization contributes enormously to health care costs associated with heart failure. Many investigators have attempted to predict hospitalization in these patients. None of these models has been highly effective in prediction, suggesting that important risk factors remain unidentified. Purpose: To assess prospectively collected medication adherence, objectively measured by the Medication Event Monitoring System, as a predictor of hospitalization in heart failure patients. Materials and methods: We used recently developed adaptive modeling methods to describe patterns of medication adherence in a sample of heart failure patients, and tested the hypothesis that poor medication adherence as determined by adaptive methods was a significant predictor of hospitalization within 6 months. Results: Medication adherence was the best predictor of hospitalization. Besides two dimensions of poor adherence (adherence pattern type and low percentage of prescribed doses taken), four other single factors predicted hospitalization: low hemoglobin, depressed ejection fraction, New York Heart Association class IV, and 12 or more medications taken daily. Seven interactions increased the predictive capability of the model: 1) pattern of poor adherence type and lower score on the Letter–Number Sequencing test, a measure of short-term memory; 2) higher number of comorbid conditions and higher number of daily medications; 3) higher blood urea nitrogen and lower percentage of prescribed doses taken; 4) lower hemoglobin and much worse perceived health compared to last year; 5) older age and lower score on the Telephone Interview of Cognitive Status; 6) higher body mass index and lower hemoglobin; and 7) lower ejection fraction and higher fatigue. Patients with none of these seven interactions had a hospitalization rate of 9.7%. For those with five of these interaction risk factors, 100% were hospitalized. The C-index (the area under the receiver-operating characteristics [ROC] curve) for the model based on the seven interactions was 0.83, indicating excellent discrimination. Conclusion: Medication adherence adds important new information to the list of variables previously shown to predict hospitalization in adults with heart failure.