We describe a physiologically significant mechanism through which interleukin-6 (IL-6) and a rising ambient Ca²⁺ interact to regulate osteoclastic bone resorption. VOXEL-based confocal microscopy of nonpermeabilized osteoclasts incubated with anti– IL-6 receptor antibodies revealed intense, strictly peripheral plasma membrane fluorescence. IL-6 receptor expression in single osteoclasts was confirmed by in situ reverse transcriptase PCR histochemistry. IL-6 (5 ng/l to 10 μg/l), but not IL-11 (10 and 100 μg/l), reversed the inhibition of osteoclastic bone resorption induced by high extracellular Ca²⁺ (15 mM). The IL-6 effect was abrogated by excess soluble IL-6 receptor (500 μg/l). Additionally, IL-6 (5 pg/l to 10 μg/l) inhibited cytosolic Ca²⁺ signals triggered by high Ca²⁺ or Ni²⁺. In separate experiments, osteoclasts incubated in 10 mM Ca²⁺ or on bone released more IL-6 than those in 1.25 mM Ca²⁺. Furthermore, IL-6 mRNA histostaining was more intense in osteoclasts in 10 or 20 mM Ca²⁺ than cells in 1.25 mM Ca²⁺. Similarly, IL-6 receptor mRNA histostaining was increased in osteoclasts incubated in 5 or 10 mM Ca²⁺. Thus, while high Ca²⁺ enhances IL-6 secretion, the released IL-6 attenuates Ca²⁺ sensing and reverses inhibition of resorption by Ca²⁺. Such an autocrine–paracrine loop may sustain osteoclastic activity in the face of an inhibitory Ca²⁺ level generated locally during resorption.