Interleukin-1 (IL-1) and transforming growth factor-alpha (TGF alpha) both stimulate bone resorption. We examined the effects that the combination of these two agents had on fetal rat long bone cultures. The 48-h resorptive response to recombinant human TGF alpha was markedly enhanced in the presence of IL-1 (either purified from stimulated human monocytes or recombinant human IL-1 alpha) compared to the effects of either agent alone. The enhanced resorptive response to the combination appeared to be dependent on prostaglandin (PG) synthesis, since it was associated with an increase in PGE concentrations in the medium and was completely blocked by either indomethacin or flufenamic acid. Substitution of TGF alpha with epidermal growth factor, a TGF alpha analog, produced identical results. We also found that IL-1 inhibited the mitogenic response of the cultures to TGF alpha. The effects of IL-1 and TGF alpha on PGE concentrations in the medium and DNA synthesis were similar in the osteoblast-like cell line MC3T3-E1. Activated macrophages and certain malignant cells are capable of producing both IL-1 and TGF alpha. Hence, similar interactions could occur in vivo and may regulate some of the effects that either immune or malignant cells have on bone.