An animal model of local allergen (airways) sensitization was employed to study the effects of rIFN-gamma administered by ultrasonic nebulization through the airways on IgE production and airways responsiveness. BALB/c mice exposed to aerosolized OVA daily for 10 days developed a predominant anti-OVA IgE response, immediate cutaneous reactivity to OVA, and increased airways responsiveness (AR). Mice were treated with rIFN-gamma, either systemically or locally via the airways, following different protocols; i.p. rIFN-gamma failed to modulate the course of OVA sensitization, although total IgE levels in the serum were decreased by 50%. Anti-OVA IgE levels remained elevated, immediate skin test responses to OVA persisted, and AR was increased. However, local treatment of the airways with nebulized rIFN-gamma caused a 66% decrease in serum anti-OVA IgE and a twofold rise in IgG2a levels. Cutaneous reactivity to OVA was reduced and AR was also normalized after nebulized rIFN-gamma. In contrast to the i.p. route, treatment with nebulized rIFN-gamma resulted in a reduction in the in vitro IgE production by lymphocytes in response to OVA and IL-4. The timing of treatment with nebulized rIFN-gamma was important in determining the immunomodulatory response. Treatment after day 7 of OVA exposure failed to modulate sensitization. Treatment regimens with nebulized rIFN-gamma that began before day 7 of OVA exposure were able to decrease anti-OVA IgE. Only treatment regimens that included 3 days of nebulized IFN-gamma before OVA sensitization caused a decrease in cutaneous reactivity and normalization of AR. The data demonstrate that both the route and timing of rIFN-gamma administration are critical factors in the immunomodulation of the immediate allergic response to allergen sensitization via the airways.