BACKGROUND: Mast cells play a critical role in inflammatory skin diseases through releasing proinflammatory mediators; however, few therapies directly target these cells. In 1878, the use of topical thymol, a now recognized potent agonist for transient receptor potential channels, was first described to treat eczema and psoriasis. OBJECTIVE: We sought to determine the mechanisms through which thymol can alter skin inflammation. METHODS: We examined the effect of topical thymol on IgE-dependent responses using a mast cell-dependent passive cutaneous anaphylaxis (PCA) model, as well as in vitro-cultured mast cells. RESULTS: Thymol dose-dependently inhibited PCA when administered topically 24 hours before antigen challenge but provoked an ear-swelling response directly on application. This direct effect was associated with local mast cell degranulation and was absent in histamine-deficient mice. However, unlike with PCA responses, there was no late-phase swelling. In vitro thymol directly triggered calcium flux in mast cells through transient receptor potential channel activation, along with degranulation and cytokine transcription. However, no cytokine protein was produced. Instead, thymol induced a significant increase in apoptotic cell death that was seen both in vitro and in vivo. CONCLUSIONS: We propose that the efficacy of thymol in reducing IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical benefits observed in early clinical reports.