Primary human immunodeficiency virus (HIV) infection should be considered a key target for HIV prevention activities. Mathematical models suggest that the primary HIV infection interval makes a disproportionate contribution to the HIV epidemic, perhaps accounting for as many as half of the existing infections at any point in time. If this is true, primary infection presents a special window of opportunity within which to exert a maximum impact on the spread of HIV. A combination of biological, behavioral, and social factors may account for the influence of primary infection on the HIV epidemic. HIV prevention measures can be focused on each of these factors. Biologically, detecting individuals early in the course of infection and offering treatment can reduce viral load and possibly an individual's infectiousness. Behaviorally, counseling newly infected persons about the importance of adopting safer practices may instill prevention behaviors at a critical time. Socially, using a network approach to notify persons exposed to those with primary infections can dampen the amplification effect of rapid HIV spread through high-risk environments. By focusing prevention efforts on the primary HIV infection interval, public health officials could increase their leverage in slowing the HIV epidemic.