The effects of cimetidine on rat adjuvant arthritis (AA) and rat osteoclast differentiation were studied. For the in vivo experiments, AA was induced by injections of Mycobacterium tuberculosis H37RA either subcutaneously into the base of the tail or into the right hind paw. The osteoclast differentiation was assessed by estimating the number of tartrate-resistant acid phosphatase-positive multinuclear cells in the bone marrow culture. Cimetidine, at the dose of 25 mg/kg body weight, reduced the paw swelling by 70% (P<0.01). Cimetidine, at 10 μM concentration, inhibited 1,25-dihydroxyvitamin D₃ (1,25[OH]₂D₃) and histamine mediated osteoclast differentiations by 40% (P<0.01) and 60% (P<0.001), respectively. Dimaprit, at 0.3 μM, stimulated the cell differentiation by 100% (P<0.01). Mepyramine reduced osteoclast differentiation, but the reduction was not statistically significant. Measurements of bone mineral density of the femur indicated that 5 mg/kg of cimetidine treated animals had 30% (P<0.01) higher mineral density in comparison with that of the AA control group that received no cimetidine. These results suggest that histamine is a potent inducer of osteoclast differentiation, at least in part, through the histamine H₂-receptor, and cimetidine has a preventive effect on articular destruction and accompanying inflammation in arthritic rats. These observations may provide critical insights into the pathogenesis of the bone pathology seen in patients with RA.