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Initiation of productive immune responses against Leishmaniadepends on the successful transition of dendritic cells (DC) from an immature to a mature phenotype. This process is characterized by high CD40 surface expression as well as interleukin-12 production, which are frequently seen in response to L. majorinfection. In vivofootpad infection of C3HeB/FeJ mice for 7 days with L. amazonensispromoted an immature CD11c+DC phenotype characterized by both significantly low CD40 surface expression and significantly decreased interleukin-12p40 production compared with L. majorinfection of these same mice. In vitroinfection of bone marrow-derived dendritic cells with L. amazonensisamastigotes resulted in rapid and significant phosphorylation of the mitogen activated protein kinase, extracellular signal-regulated kinase 1/2, observed within minutes of exposure to the parasite. Infection with L. amazonensispromastigotes led to increased 1/2 phosphorylation after 4 hours of infection compared with L. majorinfection, which correlated with promastigote transformation into amastigotes. Treatment of bone marrow-derived dendritic cells with a mitogen activated protein kinase kinase-specific inhibitor, PD98059, led to regained surface CD40 expression and interleukin-12p40 production following L. amazonensisamastigote infection compared with non-treated, infected DC. Treatment of L. amazonensis-infected mice with the highly-specific mitogen activated protein kinase kinase inhibitor, CI-1040, enhanced surface CD40 expression on CD11c+DC obtained from the draining lymph node. L. amazonensisamastigotes, through activation of extracellular signal-regulated kinase 1/2, inhibit the ability of DC to undergo proper maturation both in vitroand in vivo.