Background: The aim of our study was to examine the efficacy of short-term intravenous insulin intervention followed by oral pioglitazone/metformin therapy to prevent patients from continuous insulin application. Methods: This prospective, open-label, 4-month pilot study comprised of 14 diabetes patients (5 female, 9 male; age 60 ± 2 years; body mass index 29 ± 3.2 kg/m2; hemoglobin A1c [HbAlc] 7.6 ± 1.1%) with (1) insufficient glycemic control under a dose of metformin >1700 mg/day and/or metformin plus additional oral antidiabetes drugs (OADs) and (2) appropriate residual β-cell function. Initially, an inpatient 34 h continuous intravenous insulin infusion was performed, and metformin was given (2× 850 mg/day). Insulin was stopped, and pioglitazone 30 mg/day was added at the second inpatient day. Patients were followed for four months. Efficacy parameters [change of HbA1c, fasting blood glucose [FBG], intact proinsulin, adiponectin, and high-sensitivity C-reactive protein (hsCRP)] were assessed after initial normalization of blood glucose values by intravenous insulin and at the study end point. Results: During the acute insulin intervention, FBG levels were stabilized in all study subjects. In the following OAD treatment period, five patients showed an improvement of HbA1c > 0.5% [35.7%; seven patients remained stable (50.0%), two patients were nonresponders (14.3%)]. Fasting glucose values dropped after insulin infusion (−17.7%; p < .001). This effect was maintained during the consecutive OAD treatment period (glucose +0.3%, not significant (NS); HbA1c −6.0%; p < .05). The initial decrease in fasting intact proinsulin levels was also maintained during the study (end value −41%, p < .05). Improvements in hsCRP values (postinsulin value, −15%, NS; end value −37%; p < .05) and adiponectin values (postinsulin value +15%, NS; end value +128%; p < .001) were demonstrated at end point only after continued glitazone intake. Conclusions: Our pilot study demonstrated that a beneficial effect of a short-term intravenous insulin application on glycemic control was effectively maintained by pioglitazone/metformin treatment for at least 4 months. In addition, the oral therapy significantly improved cardiovascular risk parameters.