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Agonists of CCR1 contribute to hypersensitivity reactions and atherosclerotic lesions, possibly via the regulation of the transcription factor STAT3. CCR1 was demonstrated to use pertussis toxin-insensitive Gα14/16 to stimulate phospholipase Cβ and NF-κB, whereas both Gα14 and Gα16 are also capable of activating STAT3. The coexpression of CCR1 and Gα14/16 in human THP-1 macrophage-like cells suggests that CCR1 may use Gα14/16 to induce STAT3 activation. In this study, we demonstrated that a CCR1 agonist, leukotactin-1 (CCL15), could indeed stimulate STAT3 Tyr705 and Ser727 phosphorylation via pertussis toxin-insensitive G proteins in PMA-differentiated THP-1 cells, human erythroleukemia cells, and HEK293 cells overexpressing CCR1 and Gα14/16. The STAT3 Tyr705 and Ser727 phosphorylations were independent of each other and temporally distinct. Subcellular fractionation and confocal microscopy illustrated that Tyr705-phosphorylated STAT3 translocated to the nucleus, whereas Ser727-phosphorylated STAT3 was retained in the cytosol after CCR1/Gα14 activation. CCL15 was capable of inducing IL-6 and IL-8 (CXCL8) production in both THP-1 macrophage-like cells and HEK293 cells overexpressing CCR1 and Gα14/16. Neutralizing Ab to IL-6 inhibited CCL15-mediated STAT3 Tyr705 phosphorylation, whereas inhibition of STAT3 activity abolished CCL15-activated CXCL8 release. The ability of CCR1 to signal through Gα14/16 provides a linkage for CCL15 to regulate IL-6/STAT3–signaling cascades, leading to expression of CXCL8, a cytokine that is involved in inflammation and the rupture of atherosclerotic plaque.