The immune function of cattle infected with a primary infestation of Hypoderma lineatum is impaired during the first instar migration of the larvae. Hypodermin A (HA) is an enzyme secreted by the larvae that is implicated in immunosuppression. The response of bovine peripheral blood mononuclear cells (PBMC) to HA was examined in this study. HA blocked their proliferation in response to phytohaemagglutinin (PHA) and its effect was enhanced when cells were preincubated with HA before activation. This suggests that HA affects the lymphocyte commitment to blastogenesis during the early stages of their activation. HA also markly reduced the production of interleukin-2 (IL-2) in PHA-stimulated bovine PBMC cultures. Furthermore, indomethacin, which inhibits prostaglandin (PG) synthesis, blocked the immunosuppressive effect of HA on the PBMC proliferative response. The concentration of PGE(2) in medium of PBMC or PMA-stimulated monocyte cultures was increased by incubation with HA, Thus, the HA appeared to act by reducing IL-2 production via a prostaglandin-dependent pathway.