To investigate the immunological mechanisms of acquired resistance to tick infestation, interferon gamma (IFN-γ) deficient mice (IFN-γ −/− mice) were used to assess interleukin-4 (IL-4) and antibody production levels against tick salivary gland antigen on three successive infestations with Haemaphysalis longicornis Neumann nymphs. The engorged body weight of the ticks decreased during the second and third infestations. Similar observations were noted in IFN-γ / mice. However, the engorged body weight of the ticks from IFN-γ / mice were considerably lower than those from IFN-γ −/− mice. A marked increase in antibody production during the second and third infestations was observed indicating that IFN-γ −/− mice could acquire immunological resistance against H. longicornis nymphs. Moreover, IL-4 levels were higher during the first and third infestations but decreased during the second infestation. IL-4 levels were significantly higher in IFN-γ −/− mice than in IFN-γ / mice. We have shown here that the statistically significant high IL-4 levels observed in IFN-γ −/− mice may be a result of type 2 helper cell (Th2) polarization. However, the apparently higher IL-4 levels during the first and third infestations and the notable decline during the second infestation suggest that other cytokines or factors in the host immune system may play a part in regulating IL-4 levels.