Domestic ducks play an important role in the epidemiology of H5N1 avian influenza. Although it is known that vaccines that have a high homology with the challenge virus are able to prevent infection in ducks, little is yet known about the ability of genetically more distant vaccines in preventing infection, disease, and transmission. Here we study the effect of a widely used H5N2 vaccine (A/Chicken/Mexico/232/94/CPA) on the transmission of H5N1 virus (A/Chicken/China/1204/04) in ducks. The quantitative analyses show that despite the low level of homology between the virus and vaccine strain transmission was significantly reduced two weeks after a single or double vaccination. Mortality and disease rates were reduced markedly already one week after a single vaccination.