Background: Short-term continuous subcutaneous insulin infusion (CSII) in patients with newly diagnosed type 2 diabetes has been proved effective in improving metabolic control and b-cell function, thus inducing long-term drug-free remission. A randomized controlled trial was conducted to investigate whether CSII in combination with rosiglitazone, metformin, or a-lipoic acid separately brings about extra benefits. Patients and Methods: One hundred sixty patients with newly diagnosed type 2 diabetes were randomized to one of four treatment groups: CSII alone, CSII in combination with rosiglitazone or metformin for 3 months, or CSII with a-lipoic acid intravenous infusion for 2 weeks. Duration of CSII treatment was identical in the four groups. Glucose and lipid profiles, homeostasis model assessment (HOMA) indices, acute insulin response (AIR), intramyocellular lipid (IMCL) level, and malondialdehyde level were compared before and after intervention. Results: The near-normoglycemia rate at the third month in CSII alone and that in combination with rosiglitazone, metformin, or a-lipoic acid was 72.5%, 87.5%, 90%, and 75%, respectively (metformin group vs. CSII alone, P = 0.045). The metformin group achieved euglycemia in a shorter time (2.6 -1.3 vs. 3.7 -1.8 days, P = 0.020) with less daily insulin dosage and was more powerful in lowering total cholesterol, increasing AIR and HOMA b-cell function, whereas reduction of IMCL in the soleus was more obvious in the rosiglitazone group but not in the metformin group. The efficacy of combination with a-lipoic acid was similar to that of CSII alone. Conclusions: Short-term CSII in combination with rosiglitazone or metformin is superior to CSII alone, yet the efficacy of the two differs in some way, whereas that with a-lipoic acid might not have an additive effect.