Background and Purpose-Inflammation and infectious etiology have been implicated in the pathogenesis of dementia.We sought to investigate whether the seropositivity of common infections was associated with cognitive function. Methods-Viral burden (seropositivity for herpes simplex virus type 1 [HSV-1], herpes simplex virus type 2 [HSV-2], or cytomegalovirus [CMV]) and bacterial burden (Chlamydia pneumoniae and Mycoplasma pneumoniae) were related to cognitive status and its impairment among 383 home-dwelling elderly with cardiovascular diseases (mean age, 80 years). The Mini-Mental State Examination (MMSE) and its changes and the Clinical Dementia Rating (CDR) were used to define cognitive impairment. Results-At baseline, 0 to 1, 2, and 3 positive titers toward viruses were found in 48 (12.5%), 229 (59.8%), and 106 individuals (27.7%), respectively. MMSE points decreased with increasing viral burden (Pϭ0.03). At baseline, 58 individuals (15.1%) had cognitive impairment, which after adjustments was significantly associated with seropositivity for 3 viruses (hazard ratio, 2.5; 95% CI, 1.3 to 4.7). MMSE score decreased in 150 (43% of 348) during 12-month follow-up. After adjustment for MMSE score at baseline and with 0 to 1 seropositivities as reference (1.0), the hazard ratios were 1.8 (95% CI, 0.9 to 3.6) and 2.3 (95% CI, 1.1 to 5.0) for 2 and 3 seropositivities, respectively. The prevalence of possible or definite dementia according to CDR also increased with viral burden. No significant associations were observed between bacterial burden and cognition. Conclusions-Viral pathogen burden of HSV and CMV was associated with cognitive impairment in home-dwelling elderly persons with cardiovascular diseases. The results need to be tested in larger databases, but they may offer a preventable cause of cognitive decline.