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Chlamydia pneumoniae is a human pathogen that causes multiple diseases worldwide. Despite appropriate therapy with antichlamydial antibiotics, chronic exacerbated diseases often occur and lead to serious sequelae. The use of the macrolide clarithromycin and the fluoroquinolone ofloxacin has improved the treatment of chlamydial infection, but therapy failure is still a major problem. In this work, we studied the pretreatment with natural polyphenols and subsequent treatment with clarithromycin or ofloxacin. The phenolic compounds resveratrol and quercetin improved the antichlamydial effect of clarithromycin and ofloxacin. In particular, resveratrol at 40 μM and quercetin at 20 μM exhibited significant growth inhibition on C. pneumoniae in presence of clarithromycin or ofloxacin compared to controls. In addition, we demonstrated that both resveratrol and quercetin decreased IL-17 and IL-23 production in a time-dependent manner in C. pneumoniae-infected cells. The results showed a particularly strong inhibition of the IL-23 levels released with combined treatment of resveratrol or quercetin and ofloxacin or clarithromycin, suggesting that the combined treatment may afford a synergistic effect in controlling Chlamydia infections.