To increase comparability of vaccine clinical safety data and to improve the quality of reported data by applying the same criteria, the Hypotonic-hyporesponsive episode (HHE) Working Group has developed a case definition and guidelines for HHE applicable in study settings with different availability of resources, in health care settings that differ by availability of and access to health care, and in different geographic regions. The definition and guidelines were developed through group consensus and are grounded in both expert opinion and a systematic literature review related to the assessment of HHE as an adverse event following immunization (AEFI) and to the diagnosis of HHE in humans. The only published structured work put into the development of a case definition for HHE resulted from a U.S. public health service workshop on HHE after pertussis immunization [1]. This definition has served as the basis for consensus formation within the working group.