Toll-like receptors (TLRs) are a key part of the innate immune system that detect pathogen-associated molecular patterns (PAMPs) of microorganisms and their stimulation results in the activation of signaling pathways leading to the modulation of inflammatory and immune responses. Since psoriasis is a complex, inflammatory and immune skin disease, characterized by an abnormal immune response and increased proliferation of keratinocytes, with an increased production of proinflammatory cytokines, TLRs could play an important role in the pathogenesis of the disease. We propose to assess the modulation of TLR expression on psoriatic skin of patients treated with Adalimumab and systemic conventional therapies. We therefore recruited fifteen patients: ten were treated with adalimumab and five with systemic conventional therapies; their clinical conditions were analyzed by PASI index and skin biopsies were evaluated for TLR1 and TLR2 expression by immunohistochemistry assays. Our data suggest adalimumab is not only able to improve the clinical condition of psoriatic patients, but also to modulate TLR1 and TLR2 expression involved in psoriasis, as in healthy skin. Adalimumab is a most promising biological drug able to orchestrate immune and inflammatory responses in psoriatic lesions, recovering TLR expression on basal keratinocytes and improving clinical conditions of psoriatic patients, with no evident side effects.