Murine studies have demonstrated that the presence of indigenous gut flora is crucial for the induction of systemic immune hyporesponsiveness to antigens initially encountered within the gastrointestinal lumen. This study investigated whether increased titers of such flora, as occur in human small intestinal bacterial overgrowth, may be associated with increased suppression of systemic immune responsiveness and the possible relation between systemic and mucosal immunity in this setting. Serum total immunoglobulin (Ig), immunoglobulin subclass, and soluble interleukin-2 receptor levels and lamina propria IgA plasma cell counts were determined in 50 consecutive subjects with (N = 30) and without (N = 20) small intestinal bacterial overgrowth. Luminal IgA levels were measured in 35 of these subjects. Serum concentrations of IgG3, but not of other immunoglobulin isotypes or soluble interleukin-2 receptors, were significantly reduced in subjects with bacterial overgrowth (P < 0.0005). Small intestinal lamina propria IgA plasma cell counts (P < 0.0005) and luminal IgA concentrations (P = 0.001) were significantly increased in this group. Serum IgG3 levels were significantly inversely correlated with luminal IgA levels (P < 0.01) and fell below the lower limit of normal (0.41 g/liter) in 17/30 (56.7%) subjects with bacterial overgrowth compared to 1/20 (5.0%) subjects without (P < 0.0005). These findings document an association between small intestinal bacterial overgrowth with indigenous gut flora and reduced serum IgG3 reactivity in humans, possibly via an interaction with mucosa-related immunoregulatory mechanisms. The possibility of underlying small intestinal bacterial overgrowth should be considered in patients with serum IgG3 deficiency, especially those with compatible symptoms and/or known predisposition.