Background. Highly pathogenic avian influenza A (H5N1) virus was detected in domestic poultry in Indonesia beginning in 2003 and is now widespread among backyard poultry flocks in many provinces. The first human case of H5N1 virus infection in Indonesia was identified in July 2005. Methods. Respiratory specimens were collected from persons with suspected H5N1 virus infection and were tested by reverse-transcriptase polymerase chain reaction and viral culture. Serum samples were tested by a modified hemagglutinin inhibition antibody and/or microneutralization assay. Epidemiological, laboratory, and clinical data were collected through interviews and medical records review. Close contacts of persons with confirmed H5N1 virus infection were investigated. Results. From July 2005 through June 2006, 54 cases of H5N1 virus infection were identified, with a case-fatality proportion of 76%. The median age was 18.5 years, and 57.4% of patients were male. More than one-third of cases occurred in 7 clusters of blood-related family members. Seventy-six percent of cases were associated with poultry contact, and the source of H5N1 virus infection was not identified in 24% of cases. Conclusions. Sporadic and family clusters of cases of H5N1 virus infection, with a high case-fatality proportion, occurred throughout Indonesia during 2005-2006. Extensive efforts are needed to reduce human contact with sick and dead poultry to prevent additional cases of H5N1 virus infection.