Background: Blueberries contain high level of polyphenolic compounds with high in vitro antioxidant capacities. Their consumption has been associated with improved vascular and metabolic health.Purpose: The objective was to examine the effects of blueberry supplement consumption on metabolic syndrome (MetS) parameters and potential underlying mechanisms of action. Methods: A randomized double-blind placebo-controlled intervention trial was conducted in adults at risk of developing MetS. Participants consumed 50g daily of either a freeze-dried highbush blueberry powder (BBP) or a placebo powder for 8 weeks (n=49). MetS phenotypes were assessed at week 0, 4 and 8. Fasting blood gene expression profiles and plasma metabolomic profiles were examined at baseline and week 8 to assess metabolic changes occurring in response to the BBP. A per-protocol analysis was used. Results: Interaction effects were non-significant demonstrating that compared to the placebo, BBP had no statistically significant effect on body weight, blood pressure, fasting plasma lipid, insulin and glucose levels, insulin resistance (or sensitivity) and on glycated hemoglobin concentrations. However, there were significant within- and between-group differences including increased insulin resistance in the placebo group only, greater TG at week 4 in the BBP compared to placebo group and increased fasting insulin from week 4 to 8 in both groups. Moreover, there were significant changes in the expression of 49 genes and 35 metabolites following BBP consumption. Differentially regulated genes were clustered in immune-related pathways.Conclusion: An 8-week BBP intervention did not significantly improve traditional markers of cardiometabolic health in adults at risk of developing MetS. However, metabolically relevant changes in gene expression and metabolites suggest that clinically significant cardiometabolic changes could take longer than 8 weeks to present and/or could result from whole blueberry consumption or a higher dosage. BBP may also have an effect on factors such as immunity even within a shorter 8-week timeframe. Clinical trial registration: clinicaltrials.gov, NCT03266055, 2017, https://clinicaltrials.gov/ct2/show/NCT03266055?term=blueberry+vohl&draw=2&rank=1