Mononuclear cell fibroblast interactions in the normal human lung are poorly understood. Mononuclear cells can regulate fibroblast function and blood monocytes are known to migrate to the lung and participate in pulmonary inflammation. Thus, to clarify mononuclear cell-fibroblast interactions in the normal lung, we obtained supernatants from adherent monocytes and characterized their effect on the log phase growth of human lung fibroblasts. Monocyte supernatants inhibited fibroblast growth in a dose-dependent fashion. The inhibition was the result of an approximately 16,000 MW soluble factor(s) that was heat stable, trypsin sensitive, and chymotrypsin resistant. Elaboration of the factor(s) required monocyte protein synthesis and was not restricted to a density-defined monocyte subpopulation. The inhibitory capacity of a monocyte supernatant was directly related to its ability to stimulate fibroblast prostaglandin production. Blocking fibroblast prostaglandin production reversed the inhibition of fibroblast growth caused by monocyte supernatants. Thus, monocyte inhibition of fibroblast growth may be mediated by fibroblast prostaglandin production. Recruitment of monocytes to the lung and subsequent monocyte inhibition of fibroblast growth may be important in regulating pulmonary fibrosis.