Objectives: This study aimed to analyze the expression pattern of microRNAs (miRNAs) in white blood cells (WBC) in response to two different energy-restricted diets in patients with metabolic syndrome in the Metabolic Syndrome Reduction in Navarra-Spain (RESMENA) study. Methods: A subsample of 24 patients with metabolic syndrome features from the randomized, prospective, parallel-designed RESMENA study was selected for this analysis. The RESMENA study consisted of two dietary strategies with a 30% energy restriction: RESMENA (high meal frequency and high adherence to the Mediterranean diet) and control (based on recommendations from the American Heart Association) groups. Anthropometric and biochemical parameters as well as miRNA expression in WBC by miRNA-seq were measured before and after 8 wk of intervention. Results: A total of 49 miRNAs were differentially expressed after 8 wk of dietary intervention, 35 from the American Heart Association and 14 from the RESMENA diet. MiR-410, miR-637, miR-214, and miR-190 evidenced the most significant expression changes due to the weight loss intervention (P < 0.01). MiR-2115, -587, and -96 showed differential expressions between the two dietary strategies after 8 wk of intervention. The expression of several miRNAs was significantly associYated with anthropometric and biochemical parameters: miR-410 levels positively correlated with circulating leptin and body mass index (BMI), and miR-587 expression was associated with vascular cell adhesion protein 1. Conclusions: Different dietary patterns induce specific changes in miRNA expression in WBC. The associations of specific miRNAs with biochemical and anthropometric parameters suggest that these miRNAs might be directly or indirectly involved in the effects of weight-loss diets with different foods and macronutrient composition, and participate in the regulation of metabolic diseases. (C) 2020 Elsevier Inc. All rights reserved.