There is limited experience of both operational and financial impacts that adoption of UK pandemic influenza infection control guidance will have on the use of personal protective equipment (PPE), patients and staff. We attempted to assess these issues from a live exercise in a hospital in north-west England. During this 24 h exercise, all staff on an acute general medical ward wore PPE and adopted the procedures described in the UK pandemic influenza infection control guidance. Teams of infection control nurses observed and recorded staff behaviour and practice throughout the exercise, including staff attitudes towards the use of PPE. Although World Health Organization recommendations on the likely use of high-level PPE (FFP3 respirators) proved to be excessive, more gloves and surgical masks were used than expected. Despite pre-exercise training, many staff lacked confidence in using PPE and following infection control measures. They found PPE uncomfortable, with even basic tasks taking longer than usual. Large quantities of clinical waste were generated: an additional 12 bags (570 L) per day. The estimates of PPE usage within this exercise challenge assumptions that large amounts of high-level PPE are required, with significant implications for healthcare budgets. A programme of ongoing infection control education is needed. Healthcare in a pandemic situation is not simply a case of applying pandemic influenza infection control guidance to current practice; hospitals need to consider changing the way care and services are delivered.