Background: Observational evidence suggests that red meat intake is associated with type 2 diabetes (T2D) and cardiovascular disease incidence, but few randomized controlled trials have assessed effects of lean, unprocessed red meat intake on insulin sensitivity and other cardiometabolic risk factors., Objective: This study compared the USDA Healthy US-Style Eating Pattern, low in saturated fat and red meat (<40 g/d red meat; USDA-CON), with a modified version with an additional 150 g/d lean beef as an isocaloric replacement for carbohydrate (USDA-LB) on insulin sensitivity and cardiometabolic risk markers., Methods: Participants (7 men, 26 women; 44.4 y old) with overweight/obesity [BMI (kg/m2) = 31.3] and prediabetes and/or metabolic syndrome completed this randomized, crossover, controlled-feeding trial consisting of two 28-d treatments (USDA-CON and USDA-LB) separated by a ≥14-day washout. Insulin sensitivity (primary outcome variable), lipoprotein lipids, apolipoproteins (apoA-I and apoB), and high-sensitivity C-reactive protein (hs-CRP) (secondary outcome variables), in plasma or serum, and blood pressures were assessed at baseline and the end of each diet period., Results: USDA-LB and USDA-CON did not differ significantly in effects on whole-body insulin sensitivity and other indicators of carbohydrate metabolism, lipoprotein lipids, apoA-I and apoB, hs-CRP, and blood pressures. USDA-LB produced a shift toward less cholesterol carried by smaller LDL subfractions compared with USDA-CON [least-squares geometric mean ratios for LDL1+2 cholesterol of 1.20 (P = 0.016) and LDL3+4 cholesterol of 0.89 (P = 0.044)] and increased peak LDL time versus USDA-CON (1.01; P = 0.008)., Conclusions: Substituting lean, unprocessed beef for carbohydrate in a Healthy US-Style Eating Pattern resulted in a shift toward larger, more buoyant LDL subfractions, but otherwise had no significant effects on the cardiometabolic risk factor profile in men and women with prediabetes and/or metabolic syndrome.This trial was registered at clinicaltrials.gov as NCT03202680., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)