Epidermal Langerhans cells (LC) play a pivotal role in initiating and maintaining primary immune responses in the skin. In the present study, we asked whether peroxisome proliferator-activated receptor-alpha (PPARalpha) activation modulates LC function. Our results show that PPARalpha is expressed in immature LC and is down-regulated in mature LC suggesting that an early decrease of PPARalpha expression in LC may allow them to mature after contact with an Ag. We further show that pharmacologic PPARalpha activation inhibits LC maturation, migratory capacity, cytokine expression, and the ability to drive T cell proliferation. Moreover, PPARalpha activation inhibits NF-kappaB but not stress-activated protein kinase/JNK, p38MAPK, and ERK1/2. In conclusion, PPARalpha activation by endogenous ligands may provide a molecular signal that allows LC to remain in an immature state within the epidermis for extended periods of time despite minor environmental stimuli.