Previous studies have demonstrated that both tick saliva and Borrelia burgdorferi sensu lato antigens modulate the cytokine response of the host. In this paper, the effect of salivary gland extract (SGE) from Ixodes ricinus (L., 1758) ticks on cytokine production by primary cultures of mouse epidermal cells stimulated with Borrelia afzelii Canica, Nato, du Merle, Mazie, Baranton et Postic, 1993 spirochetes was analysed. Epidermal cells were derived from C3H/HeN mice, susceptible to Lyme disease, and BALB/c mice, which are resistant. In cultures from C3H/HeN mice, SGE down regulated production of tumour necrosis factor alpha (TNF-alpha) and up regulated Th2 cytokine, interleukin 4 (IL-4). Cultures from BALB/c mice produced higher basal levels of monitored cytokines, but their production was affected by SGE a different way. While Th2 cytokines IL-6 and IL-10 were down regulated, the effect on TNF-alpha and IL-4 was ambiguous. These results indicate that the effect of tick saliva on the epidermal cells of Lyme disease-susceptible C3H/HeN mice mirrors its effect on other cells of the immune system.