Urine albumin, high in kidney disease, predicts cardiovascular incidents and CNS white matter hyperintensity (WMH) burdens. Serum albumin - a more general biomarker which can be low in several disorders - including kidney and liver disease, malnutrition, and inflammation - also predicts cardiovascular events and is associated with cognitive impairment in several clinical populations; relations between serum albumin and WMH prevalence, however, have rarely been evaluated. In a sample of 160 individuals with alcohol use disorder (AUD), 142 infected with HIV, and 102 healthy controls, the hypothesis was tested that lower serum albumin levels would predict larger WMH volumes and worse cognitive performance irrespective of diagnosis. After considering traditional cardiovascular risk factors (e.g., age, sex, body mass index (BMI), nicotine use, hypertension, diabetes) and study-relevant variables (i.e., primary diagnoses, race, socioeconomic status, hepatitis C virus status), serum albumin survived false discovery rate (FDR)-correction in contributing variance to larger periventricular but not deep WMH volumes. This relationship was salient in the AUD and HIV groups, but not the control group. In secondary analyses, serum albumin and periventricular WMH along with age, sex, diagnoses, BMI, and hypertension were considered for hierarchical contribution to variance in performance in 4 cognitive domains. Albumin survived FDR-correction for significantly contributing to visual and verbal learning and memory performance after accounting for diagnosis. Relations between albumin and markers of liver integrity [e.g., aspartate transaminase (AST)] and blood status (e.g., hemoglobin, red blood cell count, red cell distribution width) suggest that in this sample, albumin reflects both liver dysfunction and hematological abnormalities. The current results suggest that albumin, a simple serum biomarker available in most clinical settings, can predict variance in periventricular WMH volumes and performance in visual and verbal learning and memory cognitive domains. Whether serum albumin contributes mechanistically to periventricular WMH prevalence will require additional investigation.