Interleukin‐1 (IL‐1) α and β and tumor necrosis factor (TNF) α and β are potent stimulators of bone resorption in vitro and in vivo. However, the mechanisms underlying this increased bone resorption have not been clearly defined. Increased bone resorption can result from increased activity of individual osteoclasts, increased numbers of osteoclasts, or both. Therefore, we have used a long‐term human marrow culture system that forms multinucleated cells (MNC) with the characteristics of osteoclasts to examine the effects of IL‐1 and TNF on osteoclast formation. Human recombinant IL‐1α and IL‐1β and human recombinant TNF‐α and TNF‐β stimulated MNC formation from 4‐ to 60‐fold. IL‐1α, IL‐1β, TNF‐α, and TNF‐β significantly increased MNC formation at very low concentrations: 2.5 × 10⁻¹³ M for IL‐1α and IL‐1β, 10⁻¹¹ M for TNF‐α, and 10⁻¹⁰ M for TNF‐β In addition, these cytokines enhanced MNC formation in the presence of 1,25‐dihydroxyvitamin D₃ [1,25‐(OH)₂D₃], a potent osteotropic factor that stimulates MNC formation by stimulating fusion of mononuclear precursor cells. Simultaneous addition of IL‐1 and TNF to the cultures resulted in a synergistic stimulation of MNC formation. These results suggest that: (1) IL‐1 and TNF stimulate bone resorption in part by increasing osteoclast formation and (2) an extremely low concentration of these factors can synergistically increase osteoclast formation in the absence of other factors, such as 1,25‐(OH)₂D₃. These data suggest that synergistic interactions among cytokines play an important role in maintaining bone cell activity in normal and pathologic states.