Interleukin-6 (IL-6) stimulates osteoclast formation and may be a regulator of increased resorption observed after oestrogen deficiency. We studied the role of IL-6 in bone metabolism using IL-6 deficient (IL-6-) mice. Histologically,IL-6- fetal bones were normal. In vitro, resorption was studied in two systems depending either on activity of mature osteoclasts or on osteoclast formation. Basal resorption did not differ between IL-6+ and IL-6- explants. Similarly, parathyroid-hormone-related peptide (PTHrP) stimulated osteoclast activity to the same extent inIL-6+ and IL-6- explants. In cultures depending on osteoclast formation, however, the stimulating effect of PTHrP was significantly less in the IL-6- explants, but could be restored by addition of exogenous IL-6. Using co-cultures of osteoclast-free fetal bones and bone marrow (from which osteoclasts develop), the resorption capacity of bone marrow of IL-6- mice was significantly increased (1.5-fold). In line with this, trabecular bone volume (TBV) was significantly decreased (50%) in vivo. The resorption capacity of bone marrow isolated 1 week after ovariectomy (oestrogen deficiency) was increased only in IL-6+ mice. In summary, (a) PTHrP-stimulated resorption is partly mediated by a stimulating effect of IL-6 on osteoclast formation rather than osteoclast activity; (b) osteoclast formation is increased by ovariectomy only in IL-6+ mice; and (c) IL-6 deficiency, surprisingly, leads to increased osteoclast formation with subsequent TBV reduction.