Pertussis has re-emerged in both developed and developing countries and is an ongoing public health problem, even in countries with high rates of vaccination. Pertussis encephalopathy is a known complication of the disease, but the pathophysiology of this complication and the role of the pertussis bacteria have not been elucidated. We report three confirmed cases of pertussis infant younger than 3 months of age with neurological complications including lethargy, encephalopathy, and seizures. In each case, the cerebrospinal fluid was positive for Bordetella pertussis as determined by polymerase chain reaction. One patient did not survive and two were discharged with a normal neurological exam on follow-up. The cases emphasize the importance of analyzing cerebrospinal fluid in cases of pertussis-associated encephalopathy including polymerase chain reaction.