Objective— To compare the effectiveness and acceptability of a three-injection insulin regimen with the conventional two-injection therapy in an unselected population of diabetic adolescents. Research Design and Methods— Some 205 patients aged 10–18 yr with IDDM, who were previously treated with two daily insulin injections, were included without any selection into a randomized trial. They were either switched to three (regular prebreakfast, regular prelunch, and [regular + ultralente] predinner) or remained on two ([regular + intermediary] prebreakfast and predinner) subcutaneous injections. They were evaluated after 1 yr of treatment. The major criteria of outcome of efficacy were the concentration of GHb, the frequency of severe hypoglycemia and DKA, and body weight. Results— Of the patients, 82% accepted the three-injection regimen, and 83% accepted the two-injection regimen. At entry into the trial, no significant differences appeared between the two treatment groups nor among patients refusing the allocated regimen. Significant explanatory variables predicting initial diabetes control were duration of disease and adherence to diet. GHb, decreased from 9.8 ± 0.1 to 9.3 ± 0.2% (P < 0.05) in the three-injection group, whereas it increased from 9.5 ± 0.3 to 9.8 ± 0.3% (P < 0.05) in the two-injection group, resulting in a modest (0.75%) but significant difference (P < 0.05) between GHb change in the two groups. The difference reached 1.4% (P < 0.0002) in patients with GHb > 11.2% at entry. The frequency of hypoglycemia and DKA was similar in the two groups. None of the parameters known to potentially influence glycemic control changed during the trial, and, therefore, the improvement of GHb could be attributed to the pattern of daily insulin distribution per se. Conclusions— In the general diabetic adolescent population, the efficacy of a three-injection regimen is somewhat superior to that of a conventional two-injection regimen, particularly in patients previously poorly controlled. The acceptability of this regimen being excellent, its increased use should be considered in this age-group.