Inhibition of prostaglandin (PG) production with either nonselective or selective inhibitors of cyclooxygenase-2 (COX-2) activity can induce or exacerbate salt-sensitive hypertension. This effect has been previously attributed to inhibition of intrinsic renal COX-2 activity and subsequent increase in sodium retention by the kidney. Here, we found that macrophages isolated from kidneys of high-salt–treated WT mice have increased levels of COX-2 and microsomal PGE synthase–1 (mPGES-1). Furthermore, BM transplantation (BMT) from either COX-2–deficient or mPGES-1–deficient mice into WT mice or macrophage-specific deletion of the PGE₂ type 4 (EP₄) receptor induced salt-sensitive hypertension and increased phosphorylation of the renal sodium chloride cotransporter (NCC). Kidneys from high-salt–treated WT mice transplanted with Cox2^–/– BM had increased macrophage and T cell infiltration and increased M1- and Th1-associated markers and cytokines. Skin macrophages from high-salt–treated mice with either genetic or pharmacologic inhibition of the COX-2 pathway expressed decreased M2 markers and VEGF-C production and exhibited aberrant lymphangiogenesis. Together, these studies demonstrate that COX-2–derived PGE₂ in hematopoietic cells plays an important role in both kidney and skin in maintaining homeostasis in response to chronically increased dietary salt. Moreover, these results indicate that inhibiting COX-2 expression or activity in hematopoietic cells can result in a predisposition to salt-sensitive hypertension.