The first outbreak of avian influenza A(H5N1) virus in humans occurred in Hong Kong in 1997. Infection was confirmed in 18 individuals, 6 of whom died. Infections were acquired by humans directly from chickens, without the involvement of an intermediate host. The outbreak was halted by a territory-wide slaughter of more than 1.5 million chickens at the end of December 1997. The clinical spectrum of H5N1 infection ranges from asymptomatic infection to fatal pneumonitis and multiple organ failure. Reactive hemophagocytic syndrome was the most characteristic pathologic finding and might have contributed to the lymphopenia, liver dysfunction, and abnormal clotting profiles that were observed among patients with severe infection. Rapid diagnosis with the use of reverse-transcription polymerase chain reaction and monoclonal antibody-based immunofluorescent assay were of great clinical value in the management of the outbreak. The experience of the H5N1 outbreak in Hong Kong underscores the importance of continuous surveillance of influenza virus strains in humans and in other animal species.