We have previously reported that cimetidine, a reference H2 receptor antagonist, attenuates the initial osteoclastic burst and subsequent trabecular bone loss induced by ovariectomy (ovx) in rats. This study was designed to determine whether these effects are specific to H2 antagonism. To this end, we compared the effects of two H2 receptor antagonists, cimetidine and famotidine. In addition, we analyzed the response of histamine-producing cells to these inhibitors. Seventy-two 90-day-old female Sprague-Dawley rats were ovariectomized or sham-operated, and received single daily intramuscular injections of cimetidine (125 mg/kg), famotidine (10 mg/kg), or vehicle. The animals were killed 14 days after surgery and their femurs were processed for histomorphometry. Trabecular bone volume was reduced by 30% in ovx rats and by 15% in cimetidine- and famotidine-treated rats. Architectural parameters were reduced by about 20% in ovx rats. Cimetidine and famotidine attenuated these consequences of ovx by about 50%. Trabecular connectivity was deteriorated by ovx, while cimetidine and famotidine attenuated this effect. Resorption parameters were increased by ovx, while cimetidine and famotidine prevented this increase. Kinetic bone formation parameters were increased by ovx, while cimetidine and famotidine had no influence. Neither cimetidine nor famotidine had any observable effect in sham-treated rats. Mast cell numbers increased by 250% in ovx rats and by only 40% in H2 antagonists-treated ovx rats. A resident histamine-positive, non-mast cell, population found in bone marrow was increased by 25% by ovx. Interestingly, cimetidine and famotidine reduced this population in both sham-operated and ovx rats, famotidine being more potent than cimetidine. These results show that H(2) receptor blockade partially prevents the consequences of castration on cancellous bone resorption in female rats, and strongly suggest that histamine participates in the mediator network regulating estrogen deficiency induced bone resorption. A large population of histamine-producing cells, which differ morphologically from mast cells and belong to an immature marrow population, may be a source of histamine in this model. The H(2) blockers targeted this population, and this effect appeared to explain the anti-resorptive action of the two drugs.