Background: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer’s disease (LOAD) have been reported. Objective: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. Methods: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. Results: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (≤514.8 pg/mL, OR 3.54, 95% CI 1.05–11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30–14.06) compared to the 3rd tertile (≥659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. Conclusion: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct.