This study aimed to investigate the evolution of treatment within patients with newly diagnosed epilepsy identified from a large US commercial health care database. Postdiagnosis, patient follow-up was divided into observation units defined by consecutive antiepileptic drug (AED) prescriptions. Consecutive prescriptions were compared to assess whether a change in AED regimen had occurred. Factors associated with a regimen change were explored using a logistic regression model with subject random effects. Among 5930 patients with newly diagnosed epilepsy, there was a median of one regimen change in the first year. However, patients prescribed polytherapy regimens early in the course of disease were at a substantially greater risk of a regimen change (polytherapy vs monotherapy odds ratio=10.2, 95% confidence interval=9.2-11.3). Although a seizure during the preceding 90 days significantly increased the risk of a regimen change, it was beyond the scope of the study to determine the proportion of changes directly attributable to uncontrolled seizures.