C1qTNF-Related proteins (CTRPs), a new highly conserved family of adiponectin paralogs, were recently identified as being involved in diverse processes including metabolism, host defense, apoptosis, cell differentiation, and organogenesis. However, the functional role of CTRP6 remains poorly identified. Here we provide evidence that CTRP6 induces the expression of interleukin-10 (IL-10) in macrophages. Conditioned medium from CTRP6-expressing HEK293 cells increased IL-10 expression in Raw264.7 cells. The globular domain of CTRP6 (gCTRP6) also dose-dependently increased both IL-10 mRNA and protein expression levels, with transcript levels increasing within 2 h. Furthermore, the globular domain of CTRP6 rapidly induced phosphorylation of ERK1/2 in Raw264.7 cells. Treatment with U0126, a selective inhibitor, abolished CTRP6-stimulated IL-10 induction. Taken together, there results demonstrate that CTRP6 induces expression of IL-10 via ERK1/2 activation. Considering that IL-10 is a potent anti-inflammatory cytokine that modulates inflammatory signaling pathways, CTRP6 may be a novel target for pharmacological drugs in inflammatory diseases.