Although patients with human immunodeficiency virus (HIV) infection who live in the rural United States receive less expert care and less antiretroviral treatment, the impact of living in rural areas on mortality from HIV infection is unstudied. We compared mortality rates in 327 rural and 317 urban patients with HIV infection in a retrospective cohort study using a multivariate logistic regression model. Rural patients with HIV infection were older at the end of follow-up (43.4 vs. 41.4 years, p = 0.002), and more likely white (93.0% vs. 77.9%, p < 0.001), and a greater proportion were men who have sex with men (55.5% vs. 36.1%, p < 0.001). While the mean year of diagnosis was 1994 in rural patients and 1995 in urban patients (p < 0.001), the mean CD4(+) T cell count at presentation was similar in the two groups: 376 vs. 351 cells/mul (p = 0.298). Rural patients in our cohort were more likely to receive antiretroviral medications at any CD4 count (73.7 vs. 62.1%, p =0.0016), and received PCP prophylaxis at comparable rates (23.5% vs. 25.6%,p =0.555). Mortality was higher in rural patients (10.4% vs. 6.0%, p = 0.028). The risk of mortality remained higher in rural patients when adjusting for age, sex, race, HIV risk factors, year of diagnosis, travel time, lack of insurance, and receipt of antiretroviral treatment or PCP prophylaxis in a logistic regression model (OR 2.11, 1.064 to 4.218, p = 0.047). Patients with HIV who live in rural areas have higher mortality rates than urban patients with HIV.