The volatile sulphur compound methyl mercaptan (CH3SH) is a by-product of protein metabolism and a principal component of oral malodour. This investigation examines the effect of CH3SH on the enzymatic activities of cathepsins B and G and elastase, and on the production by human gingival fibroblasts of two key factors, prostaglandin E (PGE) and cAMP, of the PGE2-cAMP-dependent pathway, which may contribute to the increased production of collagenase and tissue destruction in human periodontal disease. The results demonstrate that CH3SH alone, or in combination with interleukin-1 (IL-1) or lipopolysaccharide, can significantly enhance the secretion of PGE2, cAMP and procollagenase by human gingival fibroblasts. CH3SH also stimulated mononuclear cells to produce IL-1, which can increase cAMP production, and act in synergism with the direct effect of CH3SH on cAMP. CH3SH also significantly enhanced the activity of cathepsin B, moderately suppressed that of cathepsin G, but did not significantly affect elastase. These results provide evidence that CH3SH could be a contributing factor in the enzymatic and immunological cascade of events leading to tissue degradation in periodontal diseases.