Macrophages (Mφ) can be differentiated and polarized in vitro from human CD14⁺ monocytes under the influence of GM-CSF (GM-Mφ) and M-CSF (M-Mφ). GM-Mφs are proinflammatory and M-Mφs have an anti-inflammatory phenotype. We found selective expression of the lectin C-type lectin domain family 5 member A (CLEC5A) transcripts in GM-Mφs and the scavenger receptor CD163 molecule-like 1 (CD163L1) in M-Mφs by microarray assay. In vitro, CD163L1 expression was induced by IL-10 and M-CSF and CLEC5A by inflammatory cytokines and cell adherence. In secondary lymphoid organs, their respective expression was restricted to CD68⁺/CD163⁺ Mφs that preferentially produced either TNF (CLEC5A⁺) or IL-10 (CD163L1⁺). Mφs from healthy liver and colon tissue were mostly CD163L1⁺, and CLEC5A⁺ cells were scarce. In contrast, CLEC5A⁺ Mφs were abundant in the intestinal lamina propria from patients with inflammatory bowel disease (IBD), with higher numbers of CLEC5A⁺CD163L1⁺ found compared with those in secondary lymphoid organs. CLEC5A⁺ cells were CD14⁺CD209⁻CD11b⁺CD11c⁺TNF⁺IL-10⁺, and single positive CD163L1⁺ cells were CD14⁻CD209⁺CD11b⁻CD11c⁻TNF⁻IL-10⁺ in healthy donors and had lost the ability to produce IL-10 and to express CD209 in those with IBD. In melanomas, CLEC5A⁺ tumor-associated Mφs (TAMs) were not detected in 42% of the cases evaluated, but CD163L1⁺ TAMs were found in 100%. Similar to IBD, CD163L1⁺ TAMs expressed high levels of CD209 and produced significant amounts of IL-10, and CLEC5A⁺ TAMs were CD14^hi and produced enhanced levels of TNF in metastases. Overall, these results suggest that CD163L1 expression is associated with tissue-resident Mφs with an anti-inflammatory or anergic phenotype and that CLEC5A⁺ Mφs exhibit TNF-producing ability and might display a proinflammatory effect.