Background The impact of cytomegalovirus infection in elderly subjects remains unclear. This study examined the relationship between humoral immune response to cytomegalovirus (CMV) and all-cause mortality in a cohort of elderly hospitalised patients. Methods Data were obtained from a random sample of 715 patients (≥65 years old) admitted for any cause in a third level hospital. Serum IgG antibody against CMV was determined by enzyme-linked immunosorbent (ELISA) assay. Results A total of 480 deaths occurred in seropositive patients (n = 671) during a follow-up of 7.6 years (mean, 4.6); of which 112 patients died in-hospital or within 30 days after discharge (short-term mortality). For patients with CMV IgG antibody levels in the highest quartile compared with lower quartile, fully adjusted models showed that mortality was 1.40 times (95% CI 1.05–1.86) and 2.20 times (95% CI 1.15–4.21) higher, respectively. The exclusion of patients with cardiovascular disease (angina, myocardial infarction, heart failure, peripheral artery disease, or stroke) increases the risk of long-term (HR 2.22, 95% CI 1.36–3.62) and short-term mortality (OR 3.18, 95% CI 1.40–7.24). Conclusions Increased IgG antibody levels against CMV are associated with increased short and long-term mortality in elderly hospitalised patients, especially in patients without cardiovascular disease. Key Messages The outcome of elderly hospitalised patients in relation to CMV is unknown. We demonstrate an association between increased anti-CMV IgG levels and mortality. This association is greater in elderly patients without cardiovascular disease.