Asian H5N1 (hereafter referred to as panzootic H5N1) highly pathogenic avian influenza (HPAI) virus has caused large numbers of deaths in both poultry and wild bird populations. Recent isolates of this virus have been reported to cause disease and death in commercial ducks, which has not been seen with other HPAI viruses. However, little is known about the dissemination of this H5N1 within the organs and the cause of death in infected ducks. Nineteen 4-week-old Pekin ducks were infected with 10 ^6.7 50% egg infectious dose (EID₅₀) of HPAI A/turkey/Turkey/1/05 (H5N1, clade 2.2) in 0.1ml via the intranasal and intraocular routes. Cloacal and oropharyngeal swabs were taken daily before three animals were selected randomly and killed humanely for post-mortem examination when samples of tissues were taken for real-time RT-PCR, histopathological examination and immunohistochemistry (IHC). Clinical signs were first observed 4 days post infection (dpi) and included depression, reluctance to feed, in-coordination and torticollis resulting in the death of all the birds remaining on 5dpi. Higher levels of virus shedding was detected from oropharyngeal swabs than cloacal swabs. Real-time RT-PCR and IHC identified peak levels of virus at 2dpi in several organs. In spleen, lung, kidney, caecal tonsils, breast muscle and thigh muscle the levels were greatly reduced at 3dpi. However, the highest viral loads were detected in the heart and brain from 3dpi and coincided with the appearance of clinical signs and death. Our experimental results demonstrate the systemic spread of this HPAI H5N1 virus in Pekin ducks, and the localisation of virus in brain and heart tissue preceding death.