In a randomized, open-label, controlled cross-over trial, 107 patients with type 1 diabetes were treated with either regular human insulin or insulin lispro, a rapid-acting insulin analogue. After a lead-in period of 2 to 4 weeks, the patients were randomized to receive intensified insulin treatment with one of the insulins. NPH-human insulin was used for basal substitution in both groups. The crossover took place after 3 months of treatment. Efficacy and safety of the drugs were established by the assessment of hemoglobin A1c, pretest blood glucose, 1 and 2-hour postprandial glucose excursions, number of hypoglycemic episodes, daily insulin doses, body weight, insulin antibodies, and the number and severity of adverse events. A questionnaire comprised of four primary domains was used to measure some quality of life aspects of the patients. Both treatment regimens were well tolerated. While no differences were seen in the hemoglobin A1c values, there was a trend for a decrease in the pretest blood glucose levels and significant decreases of the 1 and 2-hour postprandial glucose excursions in the patients treated with insulin lispro. The number of hypoglycemic episodes was also significantly lower in the insulin lispro treatment period. The evaluation of the quality of life questionnaire revealed an improvement in the patients treatment satisfaction for the insulin lispro group. During treatment with insulin lispro, the basal insulin doses increased slightly. However, the total daily insulin doses decreased to a greater extent with insulin lispro as compared to regular human insulin. Human insulin-specific antibody binding values at endpoint were not different for the two treatments. In conclusion, intensive insulin treatment with insulin lispro therapy results in improved postprandial glycemic control and HbA1c levels at least equal to the treatment with regular human insulin but with less hypoglycemia and more treatment satisfaction for the patient.