OBJECTIVES Healthcare workers (HCW) are at particular risk of acquiring pertussis and transmitting the infection to high-risk susceptible patients and colleagues. In this paper, the Return On Investment (ROI) of preventively vaccinating HCW against pertussis to prevent nosocomial pertussis outbreaks is estimated using a hospital ward perspective, presuming an outbreak occurs once in 10 years. METHODS Data on the pertussis outbreak on the neonatology ward in 2004 in the Academic Medical Center Amsterdam (The Netherlands) was used to calculate control costs and other outbreak related costs. The study population was: neonatology ward staff members (n=133), parents (n=40), neonates (n=20), and newborns transferred to other hospitals (n=23). ROI is presented as the amount of Euros saved in averting outbreaks by investing one Euro in preventively vaccinating HCW. Sensitivity analysis was performed to study the robustness of the ROI. Results are presented at 2012 price level. RESULTS Total nosocomial pertussis outbreak costs were €48,682. Direct control costs (i.e. Antibiotic therapy, laboratory investigation and outbreak management control) were €11,464. Other outbreak related costs (i.e. sick leave of HCW; restrictions on the neonatology ward, savings due to reduced working force) accounted for €37,218. Vaccination costs would be €12,208. The ROI of preventively vaccinating HCW against pertussis was 1:4, meaning 4 Euros could be saved by every Euro invested in vaccinating HCW to avert outbreaks. ROI was sensitive to a lower vaccine price, considering direct control costs only, average length of stay neonates on the neonatology ward, length of patient uptake restrictions, assuming no reduced work force due to ward closer and presuming more than one outbreak to occur in 10 years’ time. CONCLUSIONS From a hospital ward perspective, preventive vaccination of HCW against pertussis to prevent nosocomial pertussis outbreaks results in a positive ROI, presuming an outbreak occurs once in 10 years.