The cytokine interleukin-10 (IL-10) is an important regulator of immune cell function, proliferation, and survival. The IL-10 receptor (IL-10R) consists of two subunits, IL-10R1 and IL-10R2, both belonging to the class II cytokine receptor superfamily. Like other members of the cytokine receptor superfamily, IL-10R stimulation leads to activation of Jak family kinases and Stat transcription factors. To identify additional signal transduction pathways used by the IL-10R, we purified 92-kDa and 100-kDa proteins that coprecipitated with IL-10R1 from IL-10-stimulated cells. Both proteins were found to be related to the 97-kDa subunit of the regulatory component of the 26S proteasome. Subsequent studies confirmed that the IL-10R1 undergoes ligand- dependent internalization and proteasome-mediated degradation. An IL-10R1 cytoplasmic domain mutant deficient for internalization exhibited prolonged signaling through Jak1 and Stat3, reinforcing the importance of receptor internalization for signal termination.