Listeriosis is a rare but severe food-borne disease, affecting unborn or newly delivered infants, the elderly, and the immunocompromised. The epidemiology of listeriosis in England and Wales changed between 2001 and 2007, with more patients ≥60 years old presenting with bacteremia (but without central nervous system [CNS] involvement). In order to explain this increase and understand the altered disease presentation, clinical, microbiological, and seasonal data on bacteremic cases of Listeria monocytogenes infection identified through national surveillance were compared with those for patients with CNS infections. Logistic regression analysis was applied while controlling for age. Bacteremic patients, who presented more frequently with gastrointestinal symptoms, were more likely to have underlying medical conditions than CNS patients. This was most marked in patients with malignancies, particularly digestive organ malignancies. Treatment to reduce stomach acid secretion modified the effect of nonmalignant underlying conditions on outcome, i.e., patients with an underlying condition who were not taking acid-suppressing medication were equally likely to have a bacteremic or a CNS infection. However, this type of therapy did not modify the effect of malignancies on the likelihood of having a bacteremic or a CNS infection. The increase in the incidence of human listeriosis among patients ≥60 years old in England and Wales between 2001 and 2007 appears to have occurred in those with cancer or other conditions whose treatment included acid-suppressing medication. Therefore, this vulnerable patient group needs specific dietary advice on avoiding risk factors for listeriosis.