Pertussis, or whooping cough, is a highly infectious, nationally notifiable respiratory disease associated with prolonged cough illness and paroxysms of coughing, inspiratory "whoop," or posttussive vomiting. Reported pertussis cases have tripled in the United States since 2001, with 25,616 probable or confirmed cases reported in 2005. This increase has been attributed to increased circulation of Bordetella pertussis, waning vaccine-induced immunity among adults and adolescents, heightened awareness of pertussis among health-care providers, increased public health reporting, and increased use of polymerase chain reaction (PCR) testing for diagnosis. To minimize the spread of pertussis, control measures must be implemented early in the course of illness when the risk for transmission is highest. However, diagnosis of pertussis is complicated by nonspecific signs and symptoms, particularly in the early catarrhal stage of disease. In addition, the lack of rapid, sensitive, and specific laboratory tests makes early and accurate identification of pertussis challenging. This report describes two hospital outbreaks and one community outbreak of respiratory illness during 2004-2006 in New Hampshire, Massachusetts, and Tennessee that were attributed initially to pertussis. However, subsequent investigations revealed negative or equivocal laboratory results and epidemiologic and clinical features atypical of pertussis, suggesting that pertussis was not the cause of these outbreaks. The findings in this report underscore the need for thorough epidemiologic and laboratory investigation of suspected pertussis outbreaks when considering extensive control measures.