Intracellular staining for cytokines and parasites, combined with two‐color flow cytometric analyses, were used to examine the frequencies of IL‐12‐, TNF‐α‐ and IL‐6‐producing macrophages in response to Leishmania major infection and/or activation with IFN‐γ/lipopolysaccharide (LPS). Inflammatory macrophages were obtained from nonimmune granulomas, initiated by the injection of polyacrylamide microbeads (Bio‐gel P‐100) into subcutaneous pouches of different mouse strains. Infection of inflammatory macrophages in vitro using metacyclic promastigotes produced identical effects on cytokine responses regardless of whether cells from genetically resistant or susceptible mouse strains were used: IL‐12 was not produced in response to infection itself, virtually every infected cell lost its ability to produce IL‐12 in response to IFN‐γ/LPS, and the IL‐6 response was partially inhibited, while the TNF‐α response of infected cells was unimpaired. Low‐multiplicity infection of inflammatory macrophages in vivo using either metacyclic promastigotes or tissue amastigotes also resulted in the complete and selective inhibition of IL‐12 responses in infected cells. These data establish the physiologic relevance of prior observations regarding the selective impairment of IL‐12 induction pathways in infected macrophages, and suggest a mechanisms for the delayed onset of cell‐mediated control mechanisms that is typical of even self‐limiting forms of leishmanial disease.