This randomized controlled trial compared the effects of a personalized dietary program (PDP) versus standard dietary advice on cardiometabolic health in a representative sample of 347 adults aged 41-70 years. The PDP used food characteristics, individual postprandial glucose and triglyceride (TG) responses, microbiomes, and health history to produce personalized food scores over an 18-week app-based program. The control group received standard care dietary advice from the USDA. Primary outcomes were serum low-density lipoprotein cholesterol (LDL-C) and TG concentrations at baseline and 18 weeks. Secondary outcomes included body weight, waist circumference, HbA1c, diet quality, and gut microbiome composition. The PDP group showed significant reductions in TGs (mean difference = −0.13 mmol l−1; P = 0.016), with no significant changes in LDL-C. Secondary outcomes, such as body weight, waist circumference, HbA1c, diet quality, and gut microbiome composition, also improved more in the PDP group compared to the control group. However, blood pressure, insulin, glucose, C-peptide, apolipoproteins A1 and B, and postprandial TGs did not differ between groups. The study concluded that a personalized nutrition program, when compared to standard dietary advice, led to significant improvements in cardiometabolic health, particularly in highly adherent participants.This randomized controlled trial compared the effects of a personalized dietary program (PDP) versus standard dietary advice on cardiometabolic health in a representative sample of 347 adults aged 41-70 years. The PDP used food characteristics, individual postprandial glucose and triglyceride (TG) responses, microbiomes, and health history to produce personalized food scores over an 18-week app-based program. The control group received standard care dietary advice from the USDA. Primary outcomes were serum low-density lipoprotein cholesterol (LDL-C) and TG concentrations at baseline and 18 weeks. Secondary outcomes included body weight, waist circumference, HbA1c, diet quality, and gut microbiome composition. The PDP group showed significant reductions in TGs (mean difference = −0.13 mmol l−1; P = 0.016), with no significant changes in LDL-C. Secondary outcomes, such as body weight, waist circumference, HbA1c, diet quality, and gut microbiome composition, also improved more in the PDP group compared to the control group. However, blood pressure, insulin, glucose, C-peptide, apolipoproteins A1 and B, and postprandial TGs did not differ between groups. The study concluded that a personalized nutrition program, when compared to standard dietary advice, led to significant improvements in cardiometabolic health, particularly in highly adherent participants.