( ), a dimorphic fungus, causes sporotrichosis. Mast cells (MCs) have been described to be involved in skin fungal infections. The role of MCs in cutaneous sporotrichosis remains largely unknown. To characterize the role and relevance of MCs in cutaneous sporotrichosis. We analyzed cutaneous sporotrichosis in wild-type (WT) mice and two different MC-deficient strains. , MCs were assessed for -induced cytokine production and degranulation after incubation with . We also explored the role of MCs in human cutaneous sporotrichosis. WT mice developed markedly larger skin lesions than MC-deficient mice (> 1.5 fold) after infection with , with significantly increased fungal burden. induced the release of tumor necrosis factor alpha (TNF), interleukin (IL)-6, IL-10, and IL-1β by MCs, but not degranulation. induced larger skin lesions and higher release of IL-6 and TNF by MCs as compared to the less virulent . In patients with sporotrichosis, TNF and IL-6 were increased in skin lesions, and markedly elevated levels in the serum were linked to disease activity. These findings suggest that cutaneous MCs contribute to skin sporotrichosis by releasing cytokines such as TNF and IL-6.