Background: Monocytes are major effector cells during Leishmania infection and any perturbance in their functions may potentially influence prospective immune responses. However functional phenotype acquired by blood monocytes in Visceral Leishmaniasis (VL) patients is poorly understood. They can acquire inflammatory or anti-inflammatory phenotypes depending upon activation signals, where later phenotype is associated with suppression of cell mediated immunity and can result in susceptibility to intracellular parasites. We speculated that VL induces a distinct monocyte phenotype which possess anti-parasitic activity and with present perspective we began to characterize activation status of blood monocytes as the basis of better parasite survival in human VL.Methods & Materials: Peripheral blood monocytes from VL and healthy controls from endemic area of Muzaffarpur, Bihar, India were compared both ex-vivo and after culture with parasite or soluble leishmanial antigen to establish activation status by assessing various pro-inflammatory and anti-inflammatory markers at phenotypic, genotypic and functional levels employing flow cytometry and RT-qPCR based assays.Results: Here we report that circulating monocytes in VL patients display anti-inflammatory phenotype composed of upregulated genes such as TGM2, C type lectin receptors, VDR, PKM, SOCS1 accompanied by downregulation in expression of inflammatory markers notably NOS2 and FCER2 at the mRNA level. These cells are non-inflammatory as they demonstrate decreased frequencies of IL6 and IL1␤ producing monocytes. We showed these are poor effector cells according to decrease in phagocytosis capacity, expression of NADPH sub-units p47 and p67 phox and ROS production. Subjects with VL had high circulating monocyte counts but they express more anti-inflammatory markers and show reduced effector functions than after treatment or healthy controls.Conclusion: These findings suggest that encounters between Leishmania and monocytes in VL promote a phenotype which is non inflammatory and is skewed towards an anti-inflammatory phenotype, that might sustain chronic infection. Strategies to manipulate the polarization of these cells may provide therapeutic advantage with appropriate pharmacological interventions.