Natural interferon-α producing cells (IPCs) are a newly characterized blood cell type, which is the major source of type I interferons in antiviral innate immune responses. The relationship between the number of circulating IPCs, HIV disease progression, and the occurrence of HIV-related complications was investigated. The study of 25 healthy donors and 54 HIV-infected subjects demonstrated a direct correlation between blood IPC number, interferon-α production, and clinical state of HIV-infected subjects. Asymptomatic long-term survivors had increased IPC number and function relative to uninfected controls and infected individuals with progressive disease. IPC numbers were markedly reduced in AIDS patients developing opportunistic infections and cancer. A negative correlation was found between the IPC number in the blood and the HIV viral load, suggesting that IPCs are important in controlling HIV replication. This study provides the first evidence that IPCs are being affected during the course of HIV infection and suggests that these cells can play a vital role in the protection against opportunistic pathogens and cancer.