Previously we demonstrated that Borrelia burgdorferi transmission by Ixodes scapularis suppressed IL-2 and IFN gamma production and promoted IL-4 production in mice. The present studies were conducted to determine whether coinfection with the human granulocytic ehrlichiosis (HE) agent would promote a Th2 cytokine response in mice. Transmission to the spleen of the agent of human granulocytic ehrlichiosis (aoHGE) and B. burgdorferi occurred 4 and 7 days, respectively, after tick infestation. Coinfection synergized to suppress splenic IL-2 production 7-14 days after tick infestion. Transmission of B. burgdorferi or aoHGE alone significantly decreased splenic IFN gamma 4-7 days after tick infestation, while coinfection suppressed IFN gamma production 7-14 days after tick infestation. Splenic IL-4 production was significantly increased 4 days after coinfection, and by day 10, aoHGE plus B. burgdorferi induced greater splenic IL-4 (57.2 pg/ml, 348% of control values) than either organism transmitted alone (aoHGE, 22.7 pg/ml, B. burgdorferi, 25.1 pg/ml). Coinfection enhanced expansion of splenic T cells, CD4+ lymphocytes and B cells while decreasing CD8+ T cells. These data demonstrate that aoHGE and B. burgdorferi, when cotransmitted, suppress a systemic IL-2 and IFN gamma response, while strongly promoting systemic IL-4 production in the susceptible host. The antigen(s) responsible for this polarization are unknown and will be the subject of future studies.