The HIV-1 accessory protein Vpr is required for efficient viral infection of macrophages and promotion of viral replication in T-cells. The biological activities of Vpr are closely tied to the interaction with DCAF1, a cellular substrate receptor of the Cullin4-RING E3 ubiquitin ligase (CRL4) of the host ubiquitin proteasome-mediated protein degradation pathway. At present, the molecular details of how Vpr usurps the protein degradation pathway have not been delineated. Here, we present the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-Uracil-DNA glycosylase (UNG2) complex. The structure reveals how Vpr engages with DCAF1 and creates the special binding interface for UNG2 recruitment, distinct from how the related Vpx proteins recruit SAMHD1 for degradation. Vpr and Vpx utilize similar N-terminal and helical regions to bind the substrate receptor, while distinctly different regions target the specific cellular substrates. Furthermore, Vpr employs molecular mimicry of DNA by a variable loop for specific recruitment of the UNG2 substrate.