The polyphenol fraction of extra-virgin olive oil may be partly responsible for its cardioprotective effects. The aim of this systematic review and meta-analysis was to evaluate the effect of high versus low polyphenol olive oil on cardiovascular disease (CVD) risk factors in clinical trials. In accordance with PRISMA guidelines, CINAHL, PubMed, Embase and Cochrane databases were systematically searched for relevant studies. Randomized controlled trials that investigated markers of CVD risk (e.g. outcomes related to cholesterol, inflammation, oxidative stress) were included. Risk of bias was assessed using the Jadad scale. A meta-analysis was conducted using clinical trial data with available CVD risk outcomes. Twenty-six studies were included. Compared to low polyphenol olive oil, high polyphenol olive oil significantly improved measures of malondialdehyde (MD: -0.07µmol/L [95%CI: -0.12, -0.02µmol/L]; I2: 88%; p = 0.004), oxidized LDL (SMD: -0.44 [95%CI: -0.78, -0.10µmol/L]; I2: 41%; P = 0.01), total cholesterol (MD 4.5 mg/dL [95%CI: -6.54, -2.39 mg/dL]; p<0.0001) and HDL cholesterol (MD 2.37 mg/dL [95%CI: 0.41, 5.04 mg/dL]; p = 0.02). Subgroup analyses and individual studies reported additional improvements in inflammatory markers and blood pressure. Most studies were rated as having low-to-moderate risk of bias. High polyphenol oils confer some CVD-risk reduction benefits; however, further studies with longer duration and in non-Mediterranean populations are required.