ObjectivesWhile epidemiological research provides strong evidence for the health benefits of increased dietary fiber (DF) intake, human intervention studies that supplement isolated DFs have shown inconsistent results. Therefore, the objective of this systematic review was to assess the effect of DF supplementation and the role of DF dose, DF physiochemical properties, intervention duration, and placebo type on immunometabolic markers of disease in intervention studies in healthy adults. MethodsWe searched several databases for intervention studies published from 1990–2018 that assessed the effect of DF on a range of well-established immunometabolic markers. Eligible studies were those that supplemented isolated DF for >2 weeks as the only intervention in at least one study arm, and reported baseline data to assess the effect of the placebo. ResultsIn total, 77 publications were included. DF supplementation significantly reduced total cholesterol (TC), low density lipoprotein (LDL), homeostatic model assessment of insulin resistance (HOMA-IR), and insulin area under the curve (AUC) in 36–49% of interventions, while less than 20% reported significant effects on C-reactive protein (CRP), interleukin-6 (IL-6), fasting glucose, glucose AUC, fasting insulin, high density lipoprotein (HDL), and triglycerides (TG). Higher DF doses were more successful in reducing CRP, TC, and LDL (40–63%), higher-viscosity and insoluble DFs for TC and LDL (≥50%), and longer interventions for CRP and glucose (50%). Placebos containing digestible carbohydrates were used in more than half of the studies, and confounded significant results for IL-6, glucose AUC, and insulin AUC. ConclusionsThe efficacy of isolated DF consumption differs vastly among immunometabolic markers assessed. Our findings suggest that DF supplementation interventions, as currently used, should focus on improving fasting cholesterol levels. However, although more research is needed to draw definitive Conclusions, higher doses, specific DF types, longer interventions, and the use of DF to replace digestible carbohydrates may improve the success of DF interventions. Funding SourcesJ.W. is a Campus Alberta Innovation Program chair for Nutrition, Microbes, and Gastrointestinal Health and recipient of grants from the Canadian Institutes of Health Research and JPI (healthy diet for a healthy life).