Background/Objectives: Oats and barley are β-glucan-rich grains that may reduce risk factors for cardiovascular disease in adults. This study was conducted to evaluate the effects of products made with either whole grain barley or whole grain oats on CVD risk factors in adults. Methods: A 6-week, double-blind, parallel-design, randomized, controlled feeding trial was conducted with 68 adults. Subjects were randomly assigned to either: (1) a control diet containing 0.8 daily servings of whole grain per 2000 kcal, (2) a diet containing 4 daily servings of whole grain oats per 2000 kcal, or (3) a diet containing 4 daily servings of whole grain barley per 2000 kcal. Markers of cardiovascular disease risk were assessed before and after treatment. Results: LDL cholesterol concentrations show a trend of statistical significance across diets (p = 0.0638), with a lowering of 8.9 mg/dL (barley) and 11.2 mg/dL (oats) compared to the control. Both whole grain diets significantly lowered total VLDL and chylomicron particles (p = 0.0272). The oat diet significantly lowered total LDL particles (p = 0.0014), small LDL particles (p = 0.0008), medium–small LDL particles (p = 0.0008), and very small LDL particles (p = 0.0009) and increased LDL particle size (p = 0.0451). The barley diet significantly lowered diastolic blood pressure (p = 0.0388) and vascular cell adhesion molecule concentrations (p = 0.0320). Conclusions: Diets containing products made from whole grain oats may improve blood lipid profiles, while diets containing products made from whole grain barley may provide additional benefits for blood pressure and inflammation.