The Gianotti-Crosti syndrome is a relatively common children dermatosis characterized by a monomorphous erythematous papular rash limited to the face and extensor surface of the arms and legs. Although the pathogenesis is still unclear, infections are considered as the most important factor. Human β-defensins are cationic antimicrobial peptides closely related to bacterial and viral infections of many epithelia. We herein report a case of Gianotti-Crosti syndrome in a 7-year-old Caucasian girl presented with prominent eruption consisting of dome-shaped lichenoid papules on her upper and lower extremities, with spontaneous resolution. Skin biopsy revealed a dense lichenoid lymphohistiocytic infiltrate and showed strong cytoplasmic immunopositivity for human β-defensin-4 in the stratum corneum, stratum granulosum, and stratum spinosum. Considering that β-defensins have been described to be induced by infections, we investigated the expression of human β-defensin-4 by immunohistochemistry in a case of Gianotti-Crosti syndrome, in order to demonstrate that it represents a cutaneous response to skin infections.