Wnt signaling plays pivotal roles in the regulation of embryogenesis and cancer development. Xenopus Dapper (Dpr) was identified as an interacting protein for Dishevelled (Dvl), a Wnt signaling mediator, and modulates Wnt signaling. However, it is largely unclear how Dpr regulates Wnt signaling. Here, we present evidence that human Dpr1, the ortholog of Xenopus Dpr, inhibits Wnt signaling. We have identified the regions responsible for the Dpr-Dvl interaction in both proteins and found that the interaction interface is formed between the DEP (Dishevelled, Egl-10, and pleckstrin) domain of Dvl and the central and the C-terminal regions of Dpr1. The inhibitory function of human Dpr1 requires both its N and C terminus. Overexpression of the C-terminal region corresponding to the last 225 amino acids of Dpr1, in contrast to wild-type Dpr1, enhances Wnt signaling, suggesting a dominant negative function of this region. Furthermore, we have shown that Dpr1 induces Dvl degradation via a lysosome inhibitor-sensitive and proteasome inhibitor-insensitive mechanism. Knockdown of Dpr1 by RNA interference up-regulates endogenous Dvl2 protein. Taken together, our data indicate that the inhibitory activity of Dpr on Wnt signaling is conserved from Xenopus to human and that Dpr1 antagonizes Wnt signaling by inducing Dvl degradation.