Many studies have demonstrated that exposure to excess diesel exhaust particles (DEP) may augment respiratory hypersensitivity responses. The potential immunosuppression of DEP was investigated in this study using a murine model. Female B6C3Fl mice ( approximately 8 weeks old) were intratracheally instilled with either saline vehicle, 1,5 or 15 mg/kg of DEP 3 times every two weeks. Positive control mice received cyclophosphamide (25 mg/kg/day, i.p.) for 4 consecutive days prior to sacrifice. The mice were sacrificed 2 or 4 weeks after the first instillation of DEP. Four days prior to sacrifice, all mice were immunized with sheep red blood cells (sRBC) intravenously. End points included body, spleen, lung, thymus and liver weights; spleen antibody-forming cell (AFC) response to sRBC; and phenotypic analysis of subpopulations of splenocytes. Exposure of mice to the high dose of DEP resulted in an increase in lung weights. In mice exposed to DEP for 2 weeks, the number of anti-sRBC IgM AFC in the spleen was decreased approximately 40% at all tested concentrations. Suppression was only observed in mice exposed to the high dose of DEP following 4 weeks of exposure. An evaluation of the spleen leukocyte subpopulations revealed a decrease in the absolute numbers of total, CD4+ and CD8+ T cells in mice exposed to DEP. Suppression of the AFC response following DEP exposure was also observed in vitro using Mishell-Dutton assay. In summary, pulmonary exposure of mice to DEP resulted in the altered spleen leukocyte subpopulations and decreased systemic T cell dependent humoral immune responses. The possible underline mechanisms of DEP-induced immunomodulation are under investigation.