Highly pathogenic avian influenza (HPAI) A (H5N1) viruses occasionally infect humans, but currently do not transmit efficiently among them. However, the risk for human pandemic influenza is a major concern should these viruses acquire the capacity for human-to-human transmission and retain their current virulence. Recently, two research teams have succeeded in modifying HPAI A (H5N1) viruses in such a way that they could be efficiently transmitted by respiratory route between ferrets, the experimental model for studying influenza virus transmission. In this article, the authors discuss the risk assessment of these mutant HPAI A (H5N1) viruses in the context of the European Union regulatory framework and recommend that laboratory-derived HPAI A (H5N1) viruses transmissible in ferrets should be handled in biosafety level 3 (BSL-3) facilities with some additional biosafety measures.