After emerging in Egypt in 2006, highly pathogenic avian influenza H5N1 viruses continued to cause outbreaks in Egyptian poultry and sporadic human infections. The strategy used by Egyptian authorities relied on vaccinating poultry, depopulating infected areas, and increasing awareness and biosecurity levels. Despite those efforts, H5N1 became endemic, and vaccine-escape variants are thought to have emerged even though commercial poultry vaccines were protective in laboratory settings. We studied the cross-reactivity of 6 commercially available H5 poultry vaccines against recent H5N1 Egyptian isolates in a field setting in Egypt. Only one vaccine based on an Egyptian H5N1 virus induced high cross-reactive antibody titers. Our results may be explained by the fact that the seed viruses in these vaccines are genetically distinct from H5N1 viruses currently circulating in Egypt. In light of our findings, we recommend that the H5N1 prevention and control strategy in Egypt be updated and reinforced. Special consideration should be given to the vaccination strategy, and the use of vaccines based on currently circulating viruses is advisable.