To assess the impact of systemic oxidative stress on humoral immune responses, we examined the relation between levels of serum 8-isoprostane and serum IgG antibodies against 17 microorganisms in the commensal oral biofilm among the ARIC population of community-dwelling adults (n = 4,717). Bivariately, serum 8-isoprostane was associated with age, race/center, education, smoking, serum triglycerides, and the extent of periodontal disease severity. Total IgG antibody directed to the oral biofilm was significantly associated with race/center, hypertension, triglycerides, periodontal disease severity, plaque, and serum 8-isoprostane. In multivariate models, the highest quartile of increased 8-isoprostane displayed marked reductions (44%) in biofilm IgG antibody in contrast to small increases in total IgG antibody level for the highest quartiles of oral bacterial burden or periodontal disease severity (19 and 12%, respectively; p < 0.0001). Increased 8-isoprostane was associated with decreased total IgG antibody (p < 0.0001) in subjects with or without extensive periodontal disease and/or biofilm and with suppression of IgG responses across the entire biofilm composition. Increased systemic oxidative stress is associated with a generalized decrease of serum IgG antibody responses to the oral biofilm. Levels of oral microbial burden, periodontitis severity, and smoking are, by comparison, minor modifiers of serum IgG responses to the commensal oral biofilm.