Topical lithium (Li) gluconate has a beneficial effect on seborrhoeic dermatitis (SD), unlike oral lithium (Li) used in psychiatry. SD is an inflammatory dermatitis associated, in most of cases, with colonization by lipophilic yeasts of the genus Malassezia. However, the exact mechanism of action of Li gluconate in SD still remains unknown. The aim of our study was to investigate the effect of topical Li on cytokine secretion and innate immunity. For this purpose, we investigated first the modulatory effect of Li on two pro-inflammatory and two anti-inflammatory cytokine secretion and second, the modulatory effect of Li on Toll-like receptor (TLR) 2 and 4 expression by unstimulated and stimulated keratinocytes. Two different skin models were used: keratinocytes in monolayer and skin explants. In some of them, inflammation was induced with LPS (1 mug/ml) or zymosan (2 mg/ml). Then the skin models were incubated with Li gluconate (Labcatal*, Montrouge, France) at three different concentrations (1.6, 3, 5 mM) determined according to viability MTT test. Expression of TNFalpha, IL6, IL10, TGFbeta1, TLR2 and TLR4 was detected by immunohistochemistry (IHC). Cytokines were quantified by ELISA methods. Our results showed that the effect of Li on keratinocytes is dose-dependent. At low concentration (1.6 mM), Li enhanced TNFalpha secretion, whereas, at higher concentration (5 mM), Li significantly enhanced IL10 expression and secretion. However, there was no significant modulation of Li on IL6 and TGFbeta1 secretion. Moreover, Li at 5 mM significantly decreased TLR2 and TLR4 expressions by differentiated keratinocytes. As Li concentration during topical treatment is probably closer to 5 mM than to 1 mM, the therapeutic effect of Li gluconate in DS may be explained by two anti-inflammatory actions: an increased expression and secretion of IL10 and a decreased expression of TLR2 and TLR4 by keratinocytes. The diminution of TLR2 expression by Li may not allow MF to trigger inflammation response in lesional skin.