We have previously postulated that mast cells (MC) may act as accessory cells in bone resorption. In this study we obtained evidence that histamine, the most abundant mediator released upon MC degranulation, is one of many factors modulating resorption. As the effect of histamine is mediated through different receptors, we tested the effects of mepyramine (1.5 mg/kg/day) and cimetidine (125 mg/kg/day), that antagonize H1 and H2 receptors, respectively. These effects were assessed morphometrically in a well-defined rat model of synchronized resorption at different stages of the process. On day 4 after induction (i.e., at the peak of resorption in this model), both agents reduced resorption significantly. Mepyramine acted by disturbing osteoclast activation and by reducing osteoclast activity (P < 0.01), while cimetidine principally reduced the size of the osteoclast population (P < 0.01). On day 6 (stage of declining resorption), the same resorption score as on day 4 was maintained in the mepyramine group, mainly through a marked increase in osteoclast activity (P < 0.01). In contrast, cimetidine continued to strongly reduce resorption (P < 0.01) and led to a further drop in the osteoclast population (P < 0.01). One day after induction, nonspecific esterase (NSE)-positive cells (putative osteoclast precursors) were significantly less numerous after treatment with the two agents. Significant changes in the MC population in the vicinity of the zone undergoing resorption occurred on days 4 and 6. The periosteal microvasculature adjacent to the reference bone zone was also markedly modified, especially in the cimetidine group. These results show that histamine intervenes in resorption through both H1 and H2 receptors. However, the mechanisms triggered by these receptors were quite different: H2 receptors appeared to be more strategic, as no replenishment of the osteoclast population occurred after the initial depletion in precursors. Histamine also appears to influence other neighbouring compartments, in which disturbances are probably linked to defective resorption. These findings support our hypothesis by which MC are accessory cells of resorption in this model.