The development and subsequent widespread use of accurate, sensitive, and relatively inexpensive diagnostic tests for infection with the human immunodeficiency virus (HIV) have been critically important in mapping the spread of the virus and managing HIV-infected individuals. Although the ELISA (for screening) and western blot (confirmatory test) techniques have, for the most part, fulfilled these criteria, interpretation of results of these tests is not always as straightforward as would be ideal. For example, what is the significance of an indeterminate western blot? How many times should the test be repeated? When can the patient be told he/she is truly HIV antibody negative? In this AIDS Commentary, Drs. John P. Phair and Steven Wolinsky of the Department of Medicine at Northwestern University Medical School address these questions and present their thoughts on these timely and extremely important issues.