The potent osteoclastogenic agent, tumor necrosis factor-alpha (TNF), exerts its biological effects via two receptors, namely TNF receptors 1 (p55r) and 2 (p75r), each present on osteoclast precursors. Thus, we asked if p55r and p75r differentially impact the osteoclastogenic process. Marrow derived from mice expressing only p55r generates substantially more osteoclasts, in the basal state, than does wild type, while marrow expressing only p75r, produces substantially fewer. Reflecting its preferential activation of p55r, exogenous TNF stimulates osteoclast formation by p55r(+/+)p75r(-/-), but not p55r(-/-)p75r(+/+), marrow. Consistent with the fact that NF-kappaB is essential for osteoclastogenesis, this transcription complex is activated, relative to wild type, in p55r(+/+)p75r(-/-) osteoclast precursors and suppressed in those expressing only p75r. Because p55r enhances, and p75r suppresses, osteoclastogenesis, we asked if their principal ligands, namely soluble and membrane-residing TNF, respectively, differentially impact basal osteoclast recruitment. We find, in contrast to the significant level of osteoclast formation in wild type marrow, osteoclastogenesis by that derived from mice expressing membrane, but not soluble, TNF, is negligible. Thus, optimal therapeutic inhibition of bone resorption may entail selective TNF receptor modulation and/or arrested cleavage of membrane TNF to its soluble form.