OBJECTIVE: The purpose of this study was to compare quality of life (QoL) and treatment satisfaction using insulin glargine plus insulin lispro with that using NPH insulin plus unmodified human insulin in adults with type 1 diabetes managed with multiple injection regimens. RESEARCH DESIGN AND METHODS: As part of a 32-week, five-center, two-way crossover study in 56 individuals with type 1 diabetes randomized to evening insulin glargine plus mealtime insulin lispro or to NPH insulin (once or twice daily) plus mealtime unmodified human insulin, the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the Audit of Diabetes Dependent Quality of Life questionnaire were completed at baseline and at weeks 16 and 32, with additional interim DTSQ measurements. RESULTS: For all patients combined, the mean baseline present QoL score was 1.3, reflecting "good" QoL. Present QoL improved with glargine + lispro but did not change with NPH + human insulin (1.6 +/- 0.1 [mean +/- SEM] vs. 1.3 +/- 0.1, difference 0.3 [95% CI 0.1-0.6]; P = 0.014). Baseline mean average weighted impact score (AWI) of diabetes on QoL was -1.8, indicating a negative impact of diabetes on QoL. The AWI score at end point improved significantly with glargine + lispro but changed little with NPH + human insulin (-1.4 +/- 0.1 vs. -1.7 +/- 0.1, 0.3 [0.0-0.6]; P = 0.033). Treatment satisfaction (DTSQ 36-0 scale score) at end point was markedly greater with glargine plus lispro compared with that for NPH plus human insulin (32.2 +/- 3.4 vs. 23.9 +/- 7.2, 8.6 [6.5-10.6]; P < 0.001). CONCLUSIONS: Insulin glargine plus insulin lispro improves treatment satisfaction, reduces the negative impact of diabetes on QoL, and improves QoL in comparison with NPH insulin plus unmodified human insulin in type 1 diabetes.