The following chapter is focused on the impact of comorbidities on the effectiveness of vaccination in older persons. Relevant comorbidities are cardiovascular diseases like hypertension, coronary artery disease or congestive heart failure, which lead to reduction of vaccine immunogenicity; or chronic obstructive pulmonary disease with a decline in lung function and a higher risk for pneumonia or infections due to influenza. End-stage renal disease has a high impact on developing infections and causes immune dysfunction over all parts of the immune system. Depression and dementia as well as psychological stress are associated with poor antibody response and a higher range of inflammation markers. Chronic inflammatory processes like rheumatoid arthritis also alter the immune system. In addition, geriatric syndromes and lowered functional status have implications for the vaccination response. Malnutrition is characterized by depletion of structural and functional proteins. This leads to a low antibody response. Negative immunomodulatory effects are also observed in vitamin D insufficiency. Frailty as well is associated with immunological changes and lowered performance in the activities of daily living, but moderate physical activity improves immune function.© 2020 S. Karger AG, Basel.