BACKGROUND: Delaying HIV care initiation may lead to greater morbidity, mortality, and further HIV transmission. Rural residence may be associated with delayed diagnosis and linkage to care, with negative clinical outcomes. OBJECTIVE: To examine the association between rural patient residence and CD4 cell count at HIV care initiation in a large HIV clinical cohort in the Southeastern United States. METHODS: We included HIV-infected patients who initiated care between 1996 and 2012 with a geocodable address and no previous history of HIV clinical care. Patient residence was categorized as urban or rural using United States Department of Agriculture Rural Urban Commuting Area codes. Multivariable linear regression models were fit to estimate the association between patient residence and CD4 cell count at HIV care initiation. RESULTS: Among 1396 patients who met study inclusion criteria, 988 had a geocodable address. Overall, 35% of patients resided in rural areas and presented to HIV care with a mean CD4 cell count of 351 cells/mm (SD, 290). Care initiation mean CD4 cell counts increased from 329 cells/mm (SD, 283) in 1996-2003 to 391 cells/mm (SD, 292) in 2008-2012 (P = 0.006). Rural in comparison with urban patients presented with lower CD4 cell counts with an unadjusted and adjusted mean difference of -48 cells/mm [95% confidence interval, -86 to -10) and -37 cells/mm (95% confidence interval: -73 to -2), respectively, consistently observed across calendar years. CONCLUSIONS: HIV care initiation at low CD4 cell counts was common in this Southeastern US cohort and more common among rural area residents.