IL-13 is a potent stimulator of alternative monocyte/macrophage activation. During alternative activation, the expression of several proteins is induced including 15-lipoxygenase (15-LO), a lipid-peroxidating enzyme and the scavenger receptor CD36. We previously reported that α(M)β(2) integrin activation or clustering suppresses the expression of both 15-LO and CD36. In this study we focused on exploring the molecular mechanisms that down-regulate CD36 expression and CD36-mediated foam cell formation in IL-13-stimulated monocytes/macrophages after α(M)β(2) activation. Our studies reveal that α(M)β(2) integrin activation inhibits the IL-13 activation of several critical pathways that are required for macrophage alternative activation; namely, blocking Jak2 and Tyk2 phosphorylation, which bind to the cytoplasmic tails of the IL-4Rα/IL-13Rα1 complex. This leads to the inhibition of tyrosine phosphorylation of Stats (Stat1, Stat3, and Stat6) and prevents the formation of a signaling complex (containing p38MAPK, PKCδ, and Stat3) that are critical for the expression of both 15-LO and CD36. Jak2-mediated Hck activation is also inhibited, thereby preventing Stats serine phosphorylation, which is essential for downstream Stat-dependent gene transcription. Moreover, inhibition of Jak2, Tyk2, or their downstream target 15-LO with antisense oligonucleotides profoundly inhibits IL-13-induced CD36 expression and CD36-dependent foam cell formation, whereas13(S) Hydroperoxyoctadecadienoic acid (HPODE), a 15-LO product and peroxisome proliferator-activated receptor-γ ligand, completely restores CD36 expression in monocytes treated with 15-LO antisense. α(M)β(2) integrin activation controls CD36 expression and foam cell formation in alternatively activated monocyte/macrophages by blocking Tyk2/Jak2 phosphorylation via a 15-LO-dependent pathway. The discovery of this mechanism helps our understanding of the potential role of alternatively activated macrophages in atherogenesis and highlights the impact of integrin α(M)β(2) on this process.