Despite all the-understandable-attention drawn in the past year by media and scientific community to the new pandemic influenza A virus H1N1, a large influenza threat continues to be posed by HPAI H5N1. In 2009, HPAI H5N1 was found in wild birds in Germany, China, Mongolia and the Russion Federation, several outbreaks of the virus in poultry were reported in Viet Nam, Hong Kong, Nepal, India, Bangladesh, Egypt, Lao DPR, and Cambodia, while H5N1 remained endemic in large areas of Indonesia. That same year also dozens of confirmed human cases were reported (WHO timeline of major events; http://www.who.int/csr/disease/avian_influenza/ ai_timeline/en/index.html). Even though the virus has so far remained restricted in its ability to infect humans and initiate efficient human-to-human transmission, its persistence and spread among wild birds and poultry holds a continual risk of the emergence of a pandemic strain. This threat can be reduced by vaccination of poultry against H5N1 as this would limit the propagation of the virus and minimize the risk of bird-to-human transmission. In addition, in case a human pandemic H5N1strain would emerge, there would be an immediate need for effective and reliable vaccines matching the pandemic strain. In the present study we evaluated the vaccine potential of a recombinant soluble H5 protein (sH5 3 ) to protect chickens and mice against a lethal infection with HPAI H5N1. The recombinant HA vaccine, which has a short development cycle, proved to be protective after a single immunization in its natural host, while a booster vaccination was needed to confer complete protection in a mammalian model. In addition, the sH5 3 induced immunity prevented viral shedding from chickens. These promising results warrant further research into the development of recombinant soluble HA as a fast, safe and effective alternative vaccine not only against H5N1, but against other influenza A viruses as well.