Increased frequency and severity of infections in the elderly have been taken as indicative of declining immune function. Dendritic cells (DCs), the most important antigen-presenting cells, play a central role in initiating and modulating immune responses. One type, DC2, arises from precursor plasmacytoid DCs (pDCs), a rare population of circulating blood cells, whose hallmark function is rapid and copious production of interferon-alpha (IFN-alpha) upon microbial challenge. We found significant decreases of the circulating pDCs during ageing in healthy adult humans, as defined both by flow cytometry and IFN-alpha generation. Mean pDC/mm3 in peripheral blood declined from 7.8 for the youngest age group (18-39 years) to 4.2 for the oldest (60-91 years; P = 0.017). IFN-alpha generation declined similarly, from 3537 to 1201 IU/ml, respectively (P = 0.006). There was also a slight decline over the age range in the amount of IFN generated per pDC (slope = -0.0087; P = 0.046). CD4+ T cells decreased by approximately 20% over the same age range (P = 0.001), while there was no change in the total lymphocyte or monocyte counts.