CCN1 (CYR61) is a matricellular protein that is highly expressed at sites of inflammation and wound repair. In these contexts, CCN1 can modify the activities of specific cytokines, enabling TNF-α to be cytotoxic without blocking NF-κB activity and enhancing the apoptotic activity of Fas ligand and TRAIL. In this paper, we show that CCN1 supports the adhesion of macrophages through integrin α M β 2 and syndecan-4, activates NFκB-mediated transcription, and induces a proinflammatory genetic program characteristic of classically activated M1 macrophages that participates in Th1 responses. The effects of CCN1 include upregulation of cytokines (TNF-α, IL-1α, IL-1β, IL-6, and IL-12b), chemokines (MIP-1α; MCP-3; growth-related oncogenes 1 and 2; and inflammatory protein 10), and regulators of oxidative stress and complement (inducible NO synthase and C3) and downregulation of specific receptors (TLR4 and IL-10Rβ) and anti-inflammatory factors (TGF-β1). CCN1 regulates this genetic program through at least two distinct mechanisms: an immediate-early response resulting from direct activation of NF-κB by CCN1, leading to the synthesis of cytokines including TNF-α and inflammatory protein 10; and a delayed response resulting from CCN1-induced TNF-α, which acts as an autocrine/paracrine mediator to activate the expression of other cytokines including IL-1β and IL-6. These results identify CCN1 as a novel component of the extracellular matrix that activates proinflammatory genes in macrophages, implicating its role in regulating macrophage function during inflammation.