OBJECTIVES: Despite extensive use of basal-bolus and premixed analog insulin therapy, real-world comparative effectiveness of the regimens has not been determined. METHODS: Patients with Type 2 diabetes at two US endocrinology practice centers were randomized to insulin glargine plus glulisine (GLAR/GLU, n=106) or analog premix (n=91). Subsequent to randomization, patients continued treatment following center's usual practice with no additional therapeutic protocols. Data collected at 0, 3, 6 and 9 months included A1C, hypoglycemia, insulin dose, concomitant medications, and therapy change. Medication costs were estimated using published average wholesale price. RESULTS: Treatment groups were comparable at baseline with mean age 56 years, 46% male, 59% Caucasian, and 38% African-American, duration of diabetes 13 years, HbA1C 9.25%, and BMI 35.8kg/m2. About 70% patients used oral hypoglycemic agent(s) during 4 months before randomization, 88% used insulin with mean daily dose of 71IU, and 29% had chart records for hypoglycemia. Mean follow-up time was 183 days. 1 patient (1%) randomized to GLAR/GLU switched to premix therapy relative to 9 (10%) randomized to premix switched to GLAR/GLU. In ITT analysis, adjusted mean follow-up HbA1C was 6.98% in GLAR/GLU vs. 7.57% in premix (d=-0.59%, p=0.009) and HbA1C reduction was 2.27% (95% CI: 1.63-2.91) vs. 1.68% (1.20-2.16). Mean number of concomitant oral anti-diabetic agents were 0.94 vs. 1.22 (d=-0.28, p=0.041). Mean daily insulin dose was 74IU vs. 85IU (d=-11, p=0.267). Hypoglycemia was recorded in charts for 36% vs. 43% (d=-7%, p=0.374) patients in GLAR/GLU vs. premix. Daily costs for all anti-diabetic medications were $9.8 in GLAR/GLU vs. $11.9 in premix (d=-$2.1, p=0.036). Treatment costs per 1% HbA1C reduction during follow-up period (183 days) were $790 for GLAR/GLU vs. $1,296 for premix. CONCLUSION: In real world practices, glargine plus glulisine, relative to analogue premix, produces improved glycemic control with lower total diabetes medication costs.