Human cytomegalovirus (CMV), a main source of morbidity in immunocompromised individuals, is usually acquired by contact between host mucosae and contaminated bodily fluids such as urine and saliva. Langerhans-type dendritic cells (LC) are the only type of dendritic cells found in the outermost layers of oral mucosae, and are therefore likely to be the first immune cells to encounter incoming CMV virions. Here we assessed the ability of a clinical-like (TB40-BAC4) and a vaccine (AD169) strain of CMV to replicate in immature and mature LC (iLC and mLC). Expression of the essential viral immediate-early proteins 1 and 2 (IE1/IE2) was low in iLC as compared to mLC, but was enhanced and prolonged when iLC were matured immediately after infection. Effective replication of viral genomes, by contrast, occurred only in mLC. Quite surprisingly, despite the absence of widespread IE1/IE2 protein synthesis and of large increases in viral genome amounts, iLC produced viral progeny to similar levels as mLC, suggesting that maturation can promote viral gene expression and genome replication (when present at infection onset), but is less supportive of viral progeny production and/or release. Finally, no difference was observed in the behavior of the two strains tested. Both iLC and mLC may thus contribute to CMV horizontal transmission in vivo by releasing virions in the saliva, while use of AD169 in orally administered vaccines may effectively activate resident LC to generate protective adaptive immune responses.