A February 2015 outbreak of highly pathogenic avian influenza (HPAI) H5N8 in a flock of commercial Pekin ducks ( Anas platyrhynchos domesticus) in California was investigated in detail. Approximately 17,349 five-wk-old ducks experienced an increased mortality from a normal of eight birds per day to 24, 18, 24, 33, and 61 birds per day, respectively, in the last 5 days prior to flock depopulation. Clinically, there was decreased water and feed consumption, and approximately 1.0% of the affected flock exhibited neurologic signs. Necropsy of five clinically ill ducks revealed pale, patchy areas on the epicardium in two birds, pale foci of necrosis in the liver of one bird, and airsacculitis in three birds. Histopathology revealed multifocal nonsuppurative encephalomyelitis, myocarditis, myositis, pancreatitis, hepatitis, and glossitis. Immunohistochemistry revealed avian influenza virus (AIV) nucleoprotein in the nucleus and cytoplasm of various cells in the aforementioned organs, as well as in the skin and feathers. Eight of the 10 sera samples tested were positive for avian influenza antibodies by agar gel immunodiffusion serology. Oropharyngeal and cloacal swabs taken from 15 birds, as well as from the lungs, livers, pancreas, and spleen, were positive for AIV by real-time reverse transcriptase (rRT) PCR. AIV was isolated and typed as Eurasian lineage HPAI H5N8, clade 18.104.22.168, by the National Veterinary Services Laboratory, Ames, IA. Extensive surveillance of birds for AIV around the 10-km zone did not reveal any additional cases. Ducks on the affected premises were humanely euthanatized by foam and composted in-house, the houses were heated to 57 C for 4 days, and swabs were taken periodically from the compost to ensure negativity for AIV by rRT-PCR. The compost and litter were then removed, and the house was pressure cleaned, disinfected, and repopulated approximately 120 days after euthanatization of the ducks.