||Intensive insulin therapy with multiple daily injections (MDI) offers superior glycemic control; however, regimen burden and hypoglycemia remain barriers to acceptance. To quantify the benefit and burden of MDI on patient satisfaction (PS), quality of life (QoL) and glycemia, we studied 388 insulin-treated patients (82 T1DM, 306 T2DM, 47% male, aged 54±11yrs, HbA1c 7.8±0.7%) randomized to open-label daily insulin glargine plus premeal glulisine (GG; n=192) or BID premix 75/25 or 70/30 (PM; n=196) for 12 wks (P1), and crossed to alternate arm for 12 wks (P2). Patients followed aggressive titration and completed questionnaires at Wks 0, 8, 12, 20 and 24, and CGMS at Wks 0, 12 and 24. Mean±SE HbA1c change for GG vs PM was -0.53±0.10% vs -0.20±0.10% for P1, and -0.25±0.10% vs +0.10±0.10% for P2 (both p<0.0001). At P1 Wk 12, 55% of GG reached HbA1c <7.0% vs 31% for PM (p<0.0001), with no differences in serious adverse events (5.4 vs 4.9%, p=0.7) or hypoglycemia. Combined mixed model P1 and P2 baseline-adjusted Wk12 mean±SE estimates are reported for PS, QoL and CGMS. PS Net Benefit scale (0–100) improved from 51.1 to 60.5±1.2 for GG, but worsened to 45.4±1.2 for PM (p< 0.0001). Overall QoL favored GG by 0.13±0.04 Z-score units (p<0.001). All 4 Net Benefit subscales favored GG (p<0.0001). PS Regimen Acceptance scale was comparable (67.3±0.5 for GG vs 66.5.±0.5 for PM, p=0.33) with 3 lifestyle and side effects subscales favoring GG (p<0.001) and 3 convenience subscales favoring PM (p<0.02). QoL scales favoring GG vs PM were perceived health, symptom distress (both p<0.0001), general health perceptions (p<0.01) and psychosocial (p<0.02). Emotional and cognitive scales were comparable. CGMS daily mean, daily SD and % time >140 mg/dL were lower for GG than PM by 12.2±2.6 mg/dl, 5.4±1.2 mg/dL and 7.3±1.6% respectively (all p< 0.0001), with no difference in CGMS % time <70 mg/dL (p=0.10). Titration with glargine plus premeal glulisine compared to premix resulted in greater satisfaction, improved quality of life, better glycemic control and less variability, without increased risk of hypoglycemia or other adverse events.