Sea Buckthorn (Hippophae rhamnoides L.) has been used in traditional medicine for the treatment of cough, indigestion, circulatory problems and pain. The associated anti-inflammatory effect of this agent is achieved via the inhibition of Nf-kB signaling, a property that has been demonstrated to effectively control the symptoms of various skin disorders, including atopic dermatitis. Accordingly, the purpose of this study was to assess the efficacy of Sea Buckthorn in reducing the production of lipopolysaccharide (LPS) activated nitric oxide (NO) by inhibiting the Nf-kB pathway, as measured by the symptoms of atopic dermatitis (AD) occurring secondarily to inflammation and immune dysregulation. Our data demonstrate that Sea Buckthorn significantly decreased the LPS-induced production of NO (p〈0.001). Atopic dermatitis was induced by repeated application of 2,4-dinitrochlorobenzene to the dorsal skin of mice. Topical application of 5% Sea Buckthorn extract improved the symptoms of AD, specifically reducing disease severity scores, scratching behaviors and epidermal thickness. When compared to the control group, animals treated with Sea Buckthorn exhibited increased serum IL-12 levels and decreased serum TNF-α, IL-4 and IL-5 levels. Such a modulation of biphasic T-helper (Th)1/Th2 cytokines may result in a reduction in serum IgE levels. Our findings suggest that mechanism of action of Sea Buckthorn in the treatment of AD is associated with a marked anti-inflammatory effect as well as an inhibition of Th2-mediated IgE overproduction via the modulation of biphasic Th1/Th2 cytokines. Such results suggest that topical Sea Buckthorn extract may prove to be a novel therapy for AD symptoms with few side effects.