Loss of CD4⁺ T cells, the hallmark of HIV pathogenesis, was suggested to be partly due to apoptosis. We recently reported that IFN-α produced by HIV-1-activated plasmacytoid dendritic cells (pDCs) contributes to CD4⁺ T cell apoptosis by the TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR)5 pathway. Here, we show that HIV-1-induced intracellular expression of IFN-α in pDCs is coupled to increased expression of IFN regulatory factor 7 and MyD88 by pDCs in vivo and in vitro. Expression of IFN-α was increased in lymphoid tonsillar tissue (LT) of patients with progressive (HIV_prog) compared with nonprogressive (HIV_NP) HIV-1 disease and to uninfected controls. LT from HIV_prog exhibited higher TRAIL and DR5 mRNA levels than LT from HIV_NP or controls. TRAIL mRNA levels in LT correlated with plasma viral load. We show that HIV-1 induces IFN-α and the TRAIL/DR5 apoptotic pathway in LT, suggesting a role for these cytokines in HIV-1 immunopathogenesis.