Resistance to the feeding activities of ixodid ticks has previously been shown to be an acquired, immunologically-mediated phenomenon in guinea-pigs, associated with cutaneous hypersensitivity to tick antigens. Also, there is circumstantial evidence to support the suggestion that epidermal Langerhans cells may play roles in the acquisition and expression of tick resistance. In this in vitro study, lymphocyte blastogenesis assays were performed using column-purified lymph node cells from naive or tick-sensitized guinea-pigs as responder cells. Syngeneic macrophages or epidermal Langerhans cells, incubated with tick salivary antigens, were used as stimulator cells. Epidermal cell populations, containing viable Langerhans cells, were prepared by two different protocols. Epidermal cell populations containing ATPase-positive, Fc receptor- and Ia-bearing cells (Langerhans cells), when incubated with tick antigen, produced detectable proliferative responses in responder cells from tick-sensitized guinea-pigs. Antigen-incubated, Ia-bearing macrophages produced similar responses. It is concluded that, as has been shown in man and the guinea-pig with other antigens, Langerhans cells, like Ia-bearing macrophages, can act as antigen-presenting accessory cells in the immunological responses of guinea-pigs to tick infestations.