The population at the U.S.-Mexico border has experienced growth, more than double the U.S. national average. Movements of populations in this region have contributed to increased incidence of certain infectious diseases. We used information on persons diagnosed with HIV during 2003 to 2006 and aged 13 years or older (n = 4,279) reported to the Centers for Disease Control and Prevention for 45 U.S. border counties. We estimated the annual percent change and rates with Poisson regression. Overall, 47% of persons diagnosed with HIV in the border region were Hispanic; 39% nonHispanic white; and 10% nonHispanic black. During 2003 to 2006, HIV diagnoses increased 7.8% per year. Increases were observed among males, particularly among men who have sex with men. Among females, HIV diagnoses remained stable but decreased among females in nonborder regions. The number of HIV diagnoses at the border has increased. To decrease incidence of HIV disease it is necessary to develop prevention and education programs specific to this region.