BackgroundSand fly saliva exposure plays an important role in immunity against leishmaniasis where it has mostly been associated with protection.Phlebotomus (Ph.) alexandritransmitsLeishmania (L.) infantum, the causative agent of visceral leishmaniasis (VL), in Iraq. Our group recently demonstrated that 20% of Operation Iraqi Freedom (OIF) deployers had asymptomatic VL (AVL) indicative of prior infection by the parasiteL.infantum. Little is known aboutPh.alexandrisaliva, and the human immune response to it has never been investigated. Here, we characterize the humoral and cellular immune response to vector saliva in OIF deployers naturally exposed to bites ofPh.alexandriand characterize their immunological profiles in association to AVL.Methodology/Principal findingsThe humoral response toPh.alexandrisalivary gland homogenate (SGH) showed that 64% of 200 OIF deployers developed an antibody response. To assess the cellular immune response to saliva, we selected a subcohort of subjects based on their post-travel (median 4 months; range 1–22 months) antibody response (SGH Antibody [Ab] positive or negative) as well as their AVL status; ten never-traveled controls were also included. Banked peripheral blood mononuclear cells (PBMC), collected ~10 years after end of deployment, were stimulated with SGH for 96 hours. The levels of IFN- γ, IL-6, IL-10, IL-13 and IL-17 were determined by ELISA. Our findings indicate that OIF deployers mounted a cellular response to SGH where the anti-SGH+ asymptomatic subjects developed the highest cytokine levels. Further, stimulation with SGH produced a mixture of pro-inflammatory and anti-inflammatory cytokines. Contrary to our hypothesis, we observed no correlation between the cellular immune response toPh.alexandriSGH and prevention from asymptomatic infection withL.infantum.Conclusions/SignificanceAs we found, although all infected deployers demonstrated persistent disease control years after deployment, this did not correlate with anti-saliva systemic cellular response. More exposure to this vector may facilitate transmission of theL.infantumparasite. Since exposure to saliva ofPh.alexandrimay alter the human immune response to bites of this vector, this parameter should be taken into consideration when considering the VL risk.