With aging, the human immune system undergoes several changes. The clinical relevance of these changes, however, is relatively unknown. We investigated immunological aspects of human aging in relation to frailty in the Doetinchem Cohort Study (DCS). We calculated a frailty index score based on 36 health parameters for each individual in the DCS with data obtained in the period 2008–2016. The frailty index was used to define three health groups (‘healthy’, ‘intermediate’, and ‘frail’), stratified by age and sex. In a subcohort (n = 289, 60–85 years, selected by balanced random sampling per frailty group), we collected blood samples between October 2016 and March 2017 to determine absolute numbers of leukocyte subsets. In addition, cytomegalovirus serostatus was assessed. C-reactive protein (CRP) levels were longitudinally assessed in four consecutive plasma samples per individual. These samples had been previously collected (1993–2013) as part of the DCS at regular time intervals and spanning a period of >15 years. We observed higher numbers of myeloid derived neutrophils and monocytes in the frail group compared to the healthy group in both men and women, and, retrospectively, consistently higher CRP concentrations over a period of >15 years. An increase in CRP concentration with age was found in women, but not in men. Frailty was not associated with cytomegalovirus serostatus or with changes in lymphoid derived T-, B-, or NK-cell numbers. Frail elderly, compared to their age- and sex-matched peers, endure a chronic and stable low-grade inflammation, which is associated with a myeloid cell lineage expansion. These findings could help to monitor clinically significant immunological decline in the elderly. •Frail elderly show continuous low-grade inflammation during at least 15 years.•This inflammation is associated with an expansion of circulating myeloid cells.•The results were observed in both sexes but were more pronounced in women.