Although studies in mice suggest that lithium enhances granulopoiesis by increasing the production of colony stimulating factor (CSF), results using human assay systems have varied. We have studied the action of lithium on the in vitro proliferation of normal human bone marrow (BM) granulocytic progenitor cells (CFUc) and on CSF production by human peripheral blood (PB) mononuclear cells (MNC). In the absence of exogenous CSF, lithium increased the number of "spontaneous" BM CFUc (P less than 0.05). This effect was abolished by removal of phagocytic cells, suggesting that lithium does not affect CFUc directly, but rather acts via a phagocytic cell. Lithium variably increased BM CFUc when PB MNC feeder layers were employed as the CSF source. This stimulation was most pronounced when the number of cells in the feeder layer was low, i.e., suboptimal CSF. Incubation with 1 meq/L lithium, increased (P less than 0.05) CSF production by PB MNC. Addition of lithium to BM cultures containing optimum CSF did not increase, but in fact decreased, the number of CFUc. These studies indicate that lithium increases CSF production by both PB and BM MNC. Furthermore, the stimulatory effects of lithium occur when CSF levels in the culture system are low.