Current US guidelines advise that antiretroviral therapy for asymptomatic HIV patients should definitely be started for those who have CD4(+) cell counts of >200 cells/ microL, but antiretroviral therapy is often not started at CD4(+) cell counts much above that level. Guidelines advocating later therapy for HIV infection have been based mainly on sparse and limited cross-sectional data and have been predicated on avoiding drug-related toxicity and viral drug resistance. However, emerging data about factors that contribute to survival and the availability of newer, less toxic drugs are eroding this position. Earlier initiation of antiretroviral therapy--namely, for patients with CD4(+) cell counts of >350 cells/ microL--may, in fact, be associated with lower mortality, better immune improvement, and less drug-related toxicity. These findings coincide with the introduction of antiretroviral drugs that have become more effective and less difficult to take. Earlier initiation of therapy may also reduce HIV transmission, an important public health consideration, and may be beneficial in terms of overall therapeutic cost-effectiveness. Given these accumulating data, we believe reconsideration of the "when-to-start" question is timely and justified.