Periodontitis is a chronic inflammatory disease affecting oral tissues. The continuous, high production of cytokines by host cells triggered by periodontopathogens is thought to be responsible for the destruction of tooth-supporting tissues. Macrophages play a critical role in this host inflammatory response to periodontopathogens. The aim of this study was to investigate the effect of non-dialyzable material prepared from cranberry juice concentrate on the pro-inflammatory cytokine response of macrophages induced by lipopolysaccharides (LPS) from Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum subsp. nucleatum, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Escherichia coli. Interleukin-1 beta (IL-1beta), IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and Regulated on Activation Normal T-cell Expressed and Secreted (RANTES) production by macrophages treated with the cranberry fraction prior to stimulation by LPS was evaluated by ELISA. Our results clearly indicate that the cranberry fraction was a potent inhibitor of the pro-inflammatory cytokine and chemokine responses induced by LPS. This suggests that cranberry constituents may offer perspectives for the development of a new therapeutic approach to the prevention and treatment of periodontitis.