The mechanism(s) by which human immunodeficiency virus (HIV) causes depletion of CD4 lymphocytes remains unknown. Evidence has been reported for a mechanism involving HIV binding to (and signaling) resting CD4 lymphocytes in lymphoid tissues, resulting in up-regulation of lymph node homing receptors and enhanced homing after these cells enter the blood, and induction of apoptosis in many of these cells during the homing process, caused by secondary signaling through homing receptors. Supportive evidence for this as a major pathogenic mechanism requires demonstration that CD4 lymphocytes in HIV(+) individuals do migrate to lymph nodes at enhanced rates. Studies herein show that freshly isolated CD4 lymphocytes labeled with (111)Indium and intravenously reinfused back into HIV(+) human donors do home to peripheral lymph nodes at rates two times faster than normal. They also home at enhanced rates to iliac and vertebral bone marrow. In contrast, two hepatitis B virus-infected subjects displayed less than normal rates of blood CD4 lymphocyte migration to peripheral lymph nodes and bone marrow. Furthermore, the increased CD4 lymphocyte homing rates in HIV(+) subjects returned to normal levels after effective, highly active antiretroviral therapy treatment, showing that the enhanced homing correlated with active HIV replication. This is the first direct demonstration of where and how fast CD4 lymphocytes in the blood traffic to tissues in normal and HIV-infected humans. The results support the theory that the disappearance of CD4 lymphocytes from the blood of HIV(+) patients is a result of their enhanced migration out of the blood (homing) and dying in extravascular tissues.