1 Department of Neurology, Hospital of the University of Pennsylvania; 2 Department of Bioengineering, School of Engineering and Applied Science; and 3 Department of Statistics, Wharton School of Business, University of Pennsylvania, Philadelphia, Pennsylvania Submitted 21 February 2006; accepted in final form 30 September 2006 Responsive, implantable stimulation devices to treat epilepsy are now in clinical trials. New evidence suggests that these devices may be more effective when they deliver therapy before seizure onset. Despite years of effort, prospective seizure prediction, which could improve device performance, remains elusive. In large part, this is explained by lack of agreement on a statistical framework for modeling seizure generation and a method for validating algorithm performance. We present a novel stochastic framework based on a three-state hidden Markov model (HMM) (representing interictal, preictal, and seizure states) with the feature that periods of increased seizure probability can transition back to the interictal state. This notion reflects clinical experience and may enhance interpretation of published seizure prediction studies. Our model accommodates clipped EEG segments and formalizes intuitive notions regarding statistical validation. We derive equations for type I and type II errors as a function of the number of seizures, duration of interictal data, and prediction horizon length and we demonstrate the model's utility with a novel seizure detection algorithm that appeared to predicted seizure onset. We propose this framework as a vital tool for designing and validating prediction algorithms and for facilitating collaborative research in this area. Address for reprint requests and other correspondence: S. Wong, Department of Neurology, 2 Ravdin Penn Epilepsy Center, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104 (E-mail: swong{at}swong.org )