Periodontal infections are hypothesized to increase the risk of adverse systemic outcomes through inflammatory mechanisms. The magnitude of effect, if any, of anti-infective periodontal treatment on systemic inflammation is unknown, as are the patient populations most likely to benefit. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to test the hypothesis that anti-infective periodontal treatment reduces systemic c-reactive protein (CRP). MEDLINE, EMBASE, CENTRAL and CINAHL databases were searched using sensitivity-enhancing search terms. Eligible RCTs enrolled patients with periodontal infection, compared a clearly defined anti-infective periodontal intervention (experimental group) to an “inactive control” (no periodontal intervention) or to an “active control” (lower treatment intensity than the experimental group). Mean differences in final CRP values at the earliest post-treatment time point (typically 1-3 months) between experimental and control groups were analyzed using random-effects regression. Among 2,753 possible studies 20 were selected, which included 2,561 randomized patients(median=57). Baseline CRP values were >3.0 mg/L in 40% of trials. Among studies with a control group receiving no treatment, the mean difference in CRP final values among experimental treatment vs. control groups was -0.37 mg/L [95%CI=-0.64, -0.11], (P=0.005), favoring experimental treatment. Trials for which the experimental group received antibiotics had stronger effects (P for interaction=0.03) and the mean difference in CRP final values among experimental treatment vs. control was -0.75 mg/L [95%CI=-1.17,-0.33]. No treatment effect was observed among studies using an active treatment comparator. Treatment effects were stronger for studies that included patients with co-morbidities vs. studies that included “systemically healthy” patients, although the interaction was not significant (P=0.48). Anti-infective periodontal treatment results in short-term modest reductions in systemic CRP.