Background: The association between cytomegalovirus (CMV) and dementia remains controversial. Previous studies have suggested that CMV serostatus, as assessed by serum immunoglobulin G, plays a role in neurodegeneration with cognitive impairment. We aimed to evaluate the association between CMV tissue-invasive end-organ diseases and moderate-to-severe dementia. Methods: The ICD 10th revision codes from the National Health Insurance Database covering the entire population of the Republic of Korea were used to classify patients into exposed (n = 687, age ≥40 years, with CMV disease) and unexposed (n = 3,435, without CMV disease) groups, matched by age and sex at a 1:5 ratio of exposed: unexposed. All non-HIV-1-infected subjects selected during 2010–2014 with a washout period of the previous 4 years were followed up until December 2016 to identify newly diagnosed cases of moderate-to-severe dementia. Results: Multivariate regression model (M3) adjusted for age, sex, low income, body mass index, transplantation status, malignant neoplasms, end-stage renal disease on dialysis, type 2 diabetes mellitus, hypertension, and dyslipidaemia showed a significantly higher incidence of dementia (odds ratio: 1.9; 95% confidence interval: 1.2–2.8) in the exposed group than that in the unexposed group. The risk of vascular dementia (2.9, 1.1–7.5) was higher than that of Alzheimer’s disease (1.6, 1.0–2.6) in the exposed group in M3. In M3, patients aged 40–59 years with CMV diseases had a significantly higher risk of all kinds of dementia than those aged 60-79 and ≥80 years (11.7, 2.5–49.4 vs. 1.8, 1.1–3.2 vs. 1.3, 0.5–2.8; P =0.025). Conclusions: CMV diseases may be associated with the risk of moderate-to-severe dementia.