Abstract Macrophages are a major component of the innate immune response, comprising the first line of defense against various intracellular pathogens, including Mycobacterium tuberculosis. In this report, we studied the factors that regulate growth of M. tuberculosis H37Rv in subpopulations of human monocyte-derived macrophages (MDMs). In healthy donors, M. tuberculosis H37Rv grew 5.6-fold more rapidly in CD14hi MDMs compared with that in CD14loCD16+ MDMs. Compared with CD14loCD16+ cells, M. tuberculosis H37Rv-stimulated CD14hi monocytes produced more IL-10 and had increased mRNA expression for c-Maf, a transcription factor that upregulates IL-10 gene expression. c-Maf small interfering RNA (siRNA) inhibited IL-10 production and growth of M. tuberculosis in CD14hi cells. Compared with CD14loCD16+ monocytes, M. tuberculosis H37Rv-stimulated CD14hi cells had increased expression of 22 genes whose promoters contained a c-Maf binding site, including hyaluronan synthase 1 (HAS1). c-Maf siRNA inhibited HAS1 expression in M. tuberculosis-stimulated CD14hi monocytes, and HAS1 siRNA inhibited growth of M. tuberculosis in CD14hi MDMs. M. tuberculosis H37Rv upregulated expression of HAS1 protein and its product, hyaluronan, in CD14hi MDMs. We conclude that M. tuberculosis grows more rapidly in CD14hi than in CD14loCD16+ MDMs because CD14hi cells have increased expression of c-Maf, which increases production of two key factors (hyaluronan and IL-10) that promote growth of M. tuberculosis.