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This article discusses cytokine patterns as potential biomarkers of vaginal inflammation, which are needed for the safety evaluation of topical microbicide products for the prevention of sexually transmitted HIV-1 infection. In order to be effective, the vaginal anti-HIV-1 microbicides should avoid proinflammatory responses that facilitate transepithelial viral penetration and replication. Pro-inflammatory and anti-inflammatory cytokines play bi-directional roles in HIV-1 pathogenesis, transmission, susceptibility and resistance. Previous research has shown that many of these key mediators of mucosal barrier function (e.g. IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TNF-receptor II, transforming growth factor β, IL-10, IL-12, IL-8, macrophage inhibitory protein 1, etc.) can be detected in the vaginal secretions of healthy or infected individuals using non-invasive sampling techniques. As part of two microbicide trials, we measured IL-1α, IL-1β, IL-1 receptor antagonist, TNF-α and IL-8 in 291 cervicovaginal lavage samples obtained before product use and at the seventh and 14th day after product use. We showed that vaginal formulations, temperature and matrix-specific factors in the vaginal fluids may interfere with cytokine detection, and therefore specific protocols must be validated for various collection procedures and cytokine assays. Our results suggest that combined patterns of cytokine dynamics rather than individual measurements might distinguish proinflammatory product-related effects in microbicide safety trials. More research is needed to establish cytokine mucosal baselines and modulation by genetic factors, sexual intercourse, menstrual cycle, exercise, hormones, stress and infections before guidelines can be established for clinical trial enrollment criteria, the prediction of side/adverse events and ultimately microbicide benefit prognostication.