Background: Diesel exhaust particles (DEPs) increase in vivo IgE and cytokine production at the human upper respiratory mucosa, exacerbating allergic inflammation. Objective: We examined the ability of DEP exposure to lead to primary sensitization of humans by driving a de novo mucosal IgE response to a neoantigen, keyhole limpet hemocyanin (KLH). Methods: Ten atopic subjects were given an initial nasal immunization with 1 mg of KLH followed by 2 biweekly nasal challenges with 100 μg of KLH. Identical nasal KLH immunization was then performed on 15 different atopic subjects, but DEPs were administered 24 hours before each KLH exposure. Results: Exposure to KLH alone led to the generation of an anti-KLH IgG and IgA humoral response, which was detected in nasal fluid samples. No anti-KLH IgE appeared in any subjects. In contrast, when challenged with KLH preceded by DEPs, 9 of the 15 subjects produced anti-KLH–specific IgE. KLH-specific IgG and IgA at levels similar to that seen with KLH alone could also be detected. Subjects who received DEPs and KLH had significantly increased IL-4, but not IFN-γ, levels in nasal lavage fluid, whereas these levels were unchanged in subjects receiving KLH alone. Conclusion: These studies demonstrate that DEPs can act as mucosal adjuvants to a de novo IgE response and may increase allergic sensitization. (J Allergy Clin Immunol 1999;1183-8.)