Abstract Objective Two insulin regimens were used to explore acute and chronic postprandial changes in glycemia, lipemia, and metabolic markers associated with increased risk of cardiovascular disease. Methods An open-label, randomized, two-period crossover study (12 weeks/period) compared a prandial regimen [premeal insulin lispro + bedtime neutral protamine Hagedorn (NPH)] with a basal regimen (twice-daily NPH). There were 30 patients (12 women and 18 men; mean age=61 years) with type 2 diabetes mellitus (mean duration=16 years) who were randomized after a 2-month lead-in with twice-daily NPH treatment. A standard lunch test meal developed according to each patient's caloric needs was administered at the end of each treatment period. Results Insulin lispro was associated with significantly lower postprandial glucose (area under the curve 0–5 h=43.54 vs. 57.65 mM/h; P<.001), elevated insulin concentrations, and acutely altered lipid fractions that included an early decrease followed by an increase in free fatty acids, lower triglycerides, elevated total cholesterol, elevated low-density lipoprotein cholesterol (LDL), and elevated high-density lipoprotein cholesterol. After 12 weeks of treatment, insulin lispro + bedtime NPH reduced hemoglobin A 1c (HbA 1c; mean±SE=7.6±0.2 vs. 8.2±0.2%; P<.001) without increasing hypoglycemia or insulin dose as compared with twice-daily NPH. Furthermore, treatment with the prandial insulin regimen resulted in lower total cholesterol, lower LDL cholesterol, and lower oxidized LDL. Conclusion Improved postprandial glycemic control, as observed in a regimen containing both prandial insulin lispro and NPH as the basal insulin, is associated with significantly lower HbA 1c and acute modulation of lipid fractions after a test meal. These biochemical modifications may potentially have a favorable impact on cardiovascular risk in patients with type 2 diabetes mellitus.