An investigation of the role of copper in bone metabolism was undertaken. Explanted calvaria from 6-day-old mice were grown for 48 h in medium with and without the addition of copper sulfate. Active resorption was found to be significantly inhibited in the presence of copper sulfate concentrations of 10(-6)M and above. Copper sulfate concentrations of 10(-5)M and above inhibited hydroxyproline, protein, and DNA synthesis. Lower concentrations wee ineffective. The effect of 5 X 10(-6)M copper sulfate on resorption was reversible. Several other compounds were tested for similar effects and at 5 X 10(-6)M were found to inhibit bone resorption in the order: copper sulfate greater than brown gold chloride greater than sodium aurothiomalate greater than zinc sulfate greater than sodium sulfate. The copper sulfate effect was twice that of sodium aurothiomalate, and sodium sulfate was not significantly inhibitory. The results suggest that the high serum copper levels associated with rheumatoid arthritis may reflect the activity of a hypothetical control mechanism of bone resorption. In the diseased state this would act to restore the normal rate of bone resorption.