Human immunodeficiency virus (HIV) is categorized into two types, HIV-1 and HIV-2. Worldwide, most HIV infections are HIV-1, whereas HIV-2 largely has been confined to persons in or from West Africa. HIV-1 and HIV-2 have the same routes of transmission, and both can cause acquired immunodeficiency syndrome (AIDS); however, HIV-2 infections should be differentiated from HIV-1 infections because they are less likely to cause AIDS and their clinical management differs. CDC's current surveillance case definition for HIV infection applies to both variants of HIV but lacks criteria for differentiating between HIV-1 and HIV-2. To enumerate and describe HIV-2 cases reported in the United States, a working case definition was developed. During 1988--June 2010, a total of 242 HIV-2 cases were reported to CDC. Of these, 166 met the working definition. These HIV-2 cases were concentrated in the Northeast (66%, including 46% in New York City) and occurred primarily among persons born in West Africa (81%). Ninety-seven of the HIV-2 cases also had a positive HIV-1 immunoblot antibody test result (e.g., Western blot). Immunoblot antibody tests currently used to confirm HIV reactive screening tests do not contain reagents specific to HIV-2 and thus are not reliable for identification of HIV-2 infections. Additional testing specific to HIV-2 should be considered if HIV-1 test results are atypical or inconsistent with clinical findings, especially for persons from West Africa. If an HIV case is reported to the health department but subsequently identified as HIV-2, health-care providers should update the case report to reflect the correct type.