To compare levels of social isolation in aging veterans with and without the human immunodeficiency virus (HIV) and determine associations with hospital admission and mortality. Longitudinal data analysis. The Veterans Aging Cohort Study (VACS), at eight VA Medical Centers nationally. Veterans aged 55 and older enrolled in VACS from 2002 to 2008 (N = 1,836). A Social Isolation Score (SIS) was created using baseline survey responses about relationship status; number of friends and family and frequency of visits; and involvement in volunteer work, religious or self-help groups, and other community activities. Scores were compared according to age and HIV status, and multivariable regression was used to assess effects of SIS on hospital admission and all-cause mortality. Mean SIS was higher for HIV-positive (HIV+) individuals, with increasing difference according to age (P = .01 for trend). Social isolation was also more prevalent for HIV+ (59%) than uninfected participants (51%, P < .001). In multivariable regression analysis of HIV+ and uninfected groups combined, adjusted for demographic and clinical features, isolation was independently associated with greater risk of incident hospitalization (hazard rate (HR) = 1.25, 95% confidence interval (CI) = 1.09-1.42) and risk of all-cause mortality (HR=1.28, 95% CI = 1.06-1.54). Risk estimates calculated for HIV+ and uninfected groups separately were not significantly different. Social isolation is associated with greater risk of hospitalization and death in HIV+ and uninfected older veterans. Despite similar effects in both groups, the population-level effect of social isolation may be greater in those who are HIV+ because of the higher prevalence of social isolation, particularly in the oldest individuals.