The factors that lead to increased production of specific IgG subclasses are still largely unknown. Recent studies suggest that increased IgG4 responses may be related to prolonged antigen exposure. We present data showing that increased IgG4 responses are found under conditions of chronic exposure to Aspergillus fumigatus (Af) antigen. IgG(total), IgG subclass, and IgE responses were studied using ELISA, CAP-FEIA, and immunoblotting techniques in patients with pulmonary aspergilloma (PA), which is a model for chronic antigen exposure, and allergic bronchopulmonary aspergillosis (ABPA), characterized by transient antigen exposure. Af-IgG1 was increased in patients with PA compared with those with ABPA. Patients with PA and IgE responses to Af and/or other inhalant allergens showed significantly higher Af-IgG4 responses than did patients with PA and negative IgE responses or patients with ABPA. Surveillance studies over time in individual patients showed concordance in Af-IgG1 and Af-IgG4 responses. Both Af-IgG1 and Af-IgG4 levels followed the course of disease progression and treatment. Immunoblotting revealed correlations between Af-IgG1 and Af-IgG4 binding to most, but not all, antigenic Af components. This study documents for the first time increased IgG4 levels under conditions of chronic exposure to fungal antigen in PA. Furthermore, a significantly higher IgG4 response was found in those patients with PA who produced IgE. The transient exposure to Af antigen during exacerbation of ABPA gives rise to transient elevations in IgG4 levels.