BACKGROUND Histamine seems to act, via H2 receptor, on inflammatory processes by stimulating interleukin (IL)-6 and matrix metalloproteinase (MMP) release. As cimetidine is an H2 receptor antagonist, the authors hypothesize that this antiulcer drug reduces IL-6, MMP-1, and MMP-9 immunoexpression in gingiva with induced periodontal disease (PD). To confirm a possible modulatory role of IL-6 on MMPs, the relationship between IL-6/MMP-1 and IL-6/MMP-9 immunoexpression was evaluated. METHODS Forty-six male rats were distributed into the cimetidine group (CimG: received daily intraperitoneal injections of 100 mg/kg of body weight of cimetidine) or the saline group (SG). PD was induced by cotton ligature around the maxillary left first molars (PDSG and PDCimG). The right molars were used as controls (SG and CimG). After 7, 15, 30, and 50 days, maxillary fragments were processed for paraffin embedding or for transmission electron microscopy. Tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in the alveolar process surface and number of IL-6, MMP-1, and MMP-9-immunolabeled cells in the gingival mucosa were quantified. Statistical analyses were performed (P ≤0.05). RESULTS In PDSG and PDCimG, gingival mucosa exhibited few collagen fibers among numerous inflammatory cells. In PDCimG, the number of TRAP-positive osteoclasts and IL-6, MMP-1, and MMP-9-immunolabeled cells was significantly lower than in PDSG at all periods. A positive correlation between IL-6/MMP-1 and IL-6/MMP-9 was detected in PDSG and PDCimG. CONCLUSION Cimetidine decreases bone loss through reduction of osteoclast number and induces reduction of IL-6, MMP-1, and MMP-9 immunoexpression, reinforcing the idea that the beneficial effect of cimetidine in PD may be due to reduction of IL-6 immunolabeling in the inflamed gingival mucosa.