White matter lesions have detrimental effects upon older adults, while serum calcium levels have been associated with elevated vascular risk and may be associated with these lesions. Depression, a serious mental disorder characterized by disturbances in calcium metabolism, may be an important contributor to any calcium-lesion relationship. This cross-sectional pilot study examined the association between serum ionized calcium (the physiologically active form of calcium) and white matter lesion volumes in a sample of depressed and non-depressed older adults (N = 42; 60 years and older). Serum ionized calcium was determined using an ion-selective electrode technique, while lesion volumes were estimated from magnetic resonance imaging using an automated expectation-maximization segmentation. A linear regression model, controlling for age and group (depression vs. comparison), showed a trend for a positive relationship between serum ionized calcium and white matter lesion volume (β = 4.34, SE = 2.27, t = 1.91, p = 0.063). Subsample analyses with depressed participants showed a significant positive relationship between higher ionic calcium and greater lesion volume (β = 6.41, SE = 2.53, t = 2.53, p = 0.018), but no association was found for non-depressed participants. Sex-specific subsample analyses showed a significant positive relationship between higher calcium and greater lesion volume in men only (β = 7.49, SE = 3.42, t = 2.19, p = 0.041). These preliminary results indicate that serum ionized calcium may be associated with white matter lesions in older adults, particularly among men and individuals with depression. Larger studies are needed to confirm these findings.