Acitretin is one of the first line drugs to treat psoriasis, though the mechanisms are not fully clear. It has been reported that psoriatic keratinocytes secreted high level of RANTES, which can induce chemotaxis and activation of T cells, thus may play an important role in the pathogenesis of psoriasis. However, the effect of acitretin on RANTES production of human keratinocytes and its possible signaling are unclear. We observed a significant inhibition of acitretin on proliferation of human keratinocytes cell line (HaCaT cells) by MTT assay. The inhibition rate of HaCaT cells growth increased gradually from 13.70 to 67.73% with acitretin concentration rising from 0.01 to 50 micromol/L. In addition, RANTES expression detected in supernatant of HaCaT cells stimulated with TNF-alpha and IFN-gamma reduced 25, 18 and 12%, respectively, when cultured with 0.1, 1 and 5 micromol/L acitretin. Furthermore, 1 micromol/L acitretin significantly decreased RANTES mRNA level. Finally, acitretin decreased the expressions of signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NFkappaB) in nuclei of HaCaT cells stimulated with TNF-alpha and IFN-gamma, which were determined by immunocytochemistry and western blot. It suggests that acitretin can inhibit proliferation and RANTES production of human epidermal keratinocytes, and the latter may be related to the inhibition of nuclear translocations of STAT1 and NFkappaB.