Myeloid dendritic cells (mDC) are depleted from the circulation and their loss inversely correlates with plasma viral load in human immunodeficiency virus (HIV) infection indicating a possible role of this phenomenon in disease pathogenesis. However, the exact mechanism of mDC loss has not been identified. To address this question we studied mDC dynamics in acute simian immunodeficiency virus (SIV) infection of rhesus macaques. Blood mDC from animals that progressed to AIDS were significantly depleted by 12 weeks of infection whereas mDC from monkeys that controlled infection were not. mDC isolated from lymph nodes at 14 days post infection were not significantly infected but did have significant levels of apoptosis. mDC from infected lymph nodes had a 4-fold increase in caspase-3 expression compared to pre-infected lymph nodes. In addition, inhibition of caspase-8, a hierarchical enzyme in the caspase cascade involving the extrinsic pathway of apoptosis, decreased caspase-3 expression by mDC. Expression of BCL-2 proteins did not differ significantly between mDC from uninfected and infected animals, whereas CD95 (Fas) was upregulated in mDC from infected monkeys, indicating a potential role for Fas/FasL in apoptosis. Our studies show that caspase-mediated apoptosis likely plays a role in the loss of mDC in pathogenic SIV infection. Further studies are underway to investigate the initiators of this apoptosis.