Although plasmacytoid dendritic cells (pDCs) are involved in HIV-1 pathogenesis, the precise mechanism of interaction between pDCs and HIV-1 in vivo is not clear. The conflicting reports in HIV-1- infected patients highlight the importance of studying the interaction between HIV-1 and pDCs in relevant in vivo models. The rag2/γC double knockout (DKO) mouse supports reconstitution of a functional human immune system in central and peripheral lymphoid organs. We report here that functional pDCs were developed in the BM and peripheral lymphoid organs in humanized DKO (DKO-hu) mice. We show that pDCs from both BM and spleen were activated and productively infected during early HIV infection. The activation level of pDCs correlated with that of CD4 + T-cell activation and apoptosis. Although CD4+ T cells were preferentially depleted, pDCs were maintained but functionally impaired in theBMand spleen of HIV-infected DKO-hu mice. We conclude that HIV-1 can efficiently infect, activate, and impair pDCs in the BM and spleen, in correlation with CD4+ T-cell depletion. The humanized mouse will serve as a relevant model to investigate the development and function of pDCs and their role during HIV-1 pathogenesis in vivo.