Background & aims: Randomised controlled trials (RCTs) in humans revealed contradictory results regarding the effect of vitamin C supplementation on blood lipids. We aimed to conduct a systematic review and meta-analysis of RCTs investigating the effect of vitamin C supplementation on total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides and to determine whether the effects are modified by the participants' or intervention characteristics. Methods: Four databases (PubMed, Embase, Scopus and Cochrane Library) were searched from inception until August 2014 for RCTs supplementing adult participants with vitamin C for >= 2 weeks and reporting changes in blood lipids. Results: Overall, vitamin C supplementation did not change blood lipids concentration significantly. However, supplementation reduced total cholesterol in younger participants (<= 52 years age) (-0.26 mmol/L, 95% CI: -0.45, -0.07) and LDL-C in healthy participants (-0.32 mmol/L, 95% CI: -0.57, -0.07). In diabetics, vitamin C supplementation reduced triglycerides significantly (-0.15 mmol/L, 95% CI: -0.30, -0.002) and increased HDL-C significantly (0.06 mmol/L, 95% CI: 0.02, all). Meta-regression analyses showed the changes in total cholesterol (beta: -0.24, CI: -0.36, -0.11) and in triglycerides (beta: -0.17, CI: -0.30, -0.05) following vitamin C supplementation were greater in those with higher concentrations of these lipids at baseline. Greater increase in HDL-C was observed in participants with lower baseline plasma concentrations of vitamin C (beta: -0.002, CI: -0.003, -0.0001). Conclusions: Overall, vitamin C supplementation had no significant effect on lipid profile. However, subgroup and sensitivity analyses showed significant reductions in blood lipids following supplementation in sub-populations with dyslipidaemia or low vitamin C status at baseline. PROSPERO Database registration: CRD42014013487, http://www.crd.york.ac.uk/prospero/. (C) 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.