Primary allergic sensitization--IgE formation after Ag exposure--is fundamental in the development of allergic respiratory disease. With the rising prevalence of asthma and allergic rhinitis, improved understanding of the determining factors for allergic sensitization is needed. Human epidemiologic studies suggest high-dose allergen exposure may paradoxically protect against sensitization. Prospective human studies of allergen dose effect on primary allergic sensitization are lacking. We prospectively examined the effect of respiratory Ag dose exposure on the rate of primary allergic sensitization to a neoantigen, keyhole limpet hemocyanin, using a unique model of human nasal allergic sensitization. Atopic human subjects were exposed to 0.1-, 10-, 1,000-, or 100,000-mug doses of intranasal keyhole limpet hemocyanin in conjunction with adjuvant intranasal diesel exhaust particles. Ag-specific IgE, IgG, and IgG4 were measured in nasal lavage samples at the conclusion of the sensitization protocol. Allergic sensitization rates for the 0.1-, 10-, 1,000-, and 100,000-mug dose groups were 0, 100, 57, and 11%, respectively. All subjects produced Ag-specific IgG with the highest levels observed in the high-dose group. These results provide direct evidence that primary allergic sensitization may be prevented by initial high levels of respiratory Ag exposure through induction of a modified, nonallergic immune response. This Ag dose effect was capable of overcoming the well-established allergic adjuvant effects of diesel exhaust particle exposure. Whether this immune response represents durable allergic tolerance is not yet known. Studies investigating the molecular mechanisms of this non-IgE response may be useful in developing therapy to prevent allergic sensitization.