Importance: Healthcare-associated outbreaks of pertussis are a growing problem, and healthcare workers (HCWs) are at increased risk for acquiring pertussis infection due to regular contact with infected patients and waning protection from pertussis vaccination in childhood or from natural pertussis infection. As such, the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) targeted HCWs as a priority group for pertussis vaccination in 2006. Prior to this recommendation, the only method to reduce transmission of pertussis after healthcare-associated exposure to persons with pertussis was post-exposure prophylaxis (PEP) with antibiotics and employee furlough. Whether HCW vaccination against pertussis will eliminate the need to provide antibiotic PEP, particularly in recently vaccinated HCWs, is unknown. Objectives: To compare the effectiveness of two strategies of PEP in HCWs exposed to pertussis who have been vaccinated with an acellular pertussis vaccine, to compare the costs of each PEP strategy and evaluate the effectiveness of vaccination to reduce the costs of control measures, and to assess for risk factors associated with healthcare-associated acquisition of pertussis by HCWs. Study Design: Open-label randomized PEP comparison study. Setting: Tertiary care children's hospital. Participants: Adult HCWs providing direct patient care (target enrolled cohort = 1,000 persons). Interventions: Following an institution-wide vaccination campaign, eligible HCWs will be consented to participate in the PEP comparison. Following vaccination, monitoring for exposures to pertussis will occur. Once identified as an exposure to a person with pertussis, study participants will be randomized to one of two proposed PEP strategies: a) provision of universal antibiotic therapy or b) careful daily observation of vaccinated HCWs for the development of symptoms without antibiotic prescription. In addition, following identification of an exposure to pertussis, affected study participants will complete a survey targeted at identifying specific patient care duties performed by the exposed HCW during contact with the index case. Outcome Measures: Evidence of secondary pertussis infection via serologic, polymerase chain reaction (PCR), and culture testing in each PEP arm. Following conduct of the main trial, an assessment of the costs of various pertussis prevention strategies as well as the identification of specific risk factors for HCW acquisition of pertussis will be conducted.