Toll-like receptor 4 (TLR-4) plays a crucial role in the pathophysiology of several age-related diseases. Although poorer function of circulating myeloid dendritic cells (mDCs) has been reported in the elderly, data on TLR-4 function in these cells in older people are lacking. Here, we investigated TLR-4 functionality in the elderly by ex vivo analysis of cytokine production of mDCs in response to LPS in 39 younger (23–34 years) and 61 older (62–77 years) healthy people using flow cytometry. We matched these subjects for Cytomegalovirus (CMV)-serostatus because a latent infection with this ubiquitous herpesvirus is known to affect numerous immune parameters. We found that TLR-4-dependent production of IL-6 and TNF was strongly stimulated in circulating mDCs from the elderly. However, mDCs of more than half of the young donors failed to respond in the same way. This was related to their already highly activated ex vivo state, predominantly observed in CMV-seropositive young donors and associated with lower CMV-specific IgG titres. This may reflect an increasingly important requirement for control of CMV infection throughout life. These data suggest that TLR-4 agonists may be the adjuvants of choice for elderly people, most of whom are CMV-positive, and whose responses to immunization are frequently impaired.