Intestinal MΦ play an important role in maintaining guthomeostasis. However, little is known about thesecells, their precursors, and their role in intestinal inflammation.Here, we characterize the CD14 mononuclear cell populations in intestinal mucosa and blood in patients with CD. Among the LP CD14+ MΦ, we identifiedthree distinct HLA-DR+ -expressing subsets. Compared with uninflamed, inflamed mucosa contained a markedincrease in the proportion of the CD14hiHLA-DRdim cellular subset. This subset resembled the classical bloodmonocytes with low CD16, HLA-DR, and CX3CR1 expression. Classical monocytes migrated efficiently towardCCL2 and released the highest levels of MMP-1and proinflammatory cytokines when stimulated withimmune complexes or LPS. Our findings strongly suggestthat it is the classical and not the intermediate ornonclassical monocytes that are the precursors tothe dominating intestinal CD14hiHLA-DRdim subset.This enhances our understanding of CD pathologyand may provide new options in treatment.