Taurine (TAU), a free amino acid ubiquitously found in all mammalian tissues, has shown effectiveness against biochemical, functional and morphological alterations associated with diabetes mellitus and with insulin (INS) resistance in animal models of diabetes. The present study was designed to investigate whether adding TAU to a therapeutic regimen with drugs currently used for the treatment of diabetes in humans will favorably impact on indices of hyperglycemia, hypoinsulinemia, hyperlipidemia and oxidative stress and on the morphology and cytoskeletal organization of circulating erythrocytes (RBCs). In the study, Sprague-Dawley rats, 225-230 g, made diabetic with an i.p. dose of streptozotocin (STZ, 60 mg/kg), were assigned to groups receiving on day 14 (a) a single compound (captopril (CAP), metformin (MET), lovastatin (LOV), TAU or the TAU analog thiotaurine (THIO)); (b) two compounds (TAU-CAP, TAU-LOV or TAU-MET); or (c) three compounds (TAU-MET-CAP or TAU-MET-LOV) by intragastric gavage. Additional groups received only physiological saline orally (the control group), only STZ (the diabetic group) or only INS subcutaneously (the reference group). Except for STZ, all other treatments were carried out until day 56 of the study. On day 57, all the animals were sacrificed by decapitation and their blood samples collected in heparinized tubes for the subsequent isolation of plasma and RBCs. Relative to changes in diabetic rats, all compounds but LOV lowered the plasma glucose, plasma free hemoglobin (Hb) and blood HbA _1c levels. Likewise, all the compounds raised the plasma INS, lowered the plasma cholesterol and triglycerides levels, and attenuated oxidative stress (based on decreased plasma malondialdehyde and GSSG levels, and increased GSH, GSH/GSSG ratios and activities of antioxidant enzymes). The attenuating potency generally decreased in the order INS>MET>THIO≥TAU>CAP>LOV. Bitherapy was more effective than monotherapy, with the potency order being TAU-MET>TAU-CAP>TAU-LOV; and tritherapy usually provided an equivalent or greater protection than bitherapy with TAU-MET. These results correlated well with the corresponding improvement in body weight gains over an 8-week period relative to untreated diabetic rats, and with the prevention by INS, MET, LOV and TRIO of the formation of spiculated RBCs and segregation of the RBC spectrin. The present results strongly suggest that supplementation of a conventional antidiabetic drug regimen with TAU can lead to an improvement of the effects of the regimen against diabetes-related body weight loss and cellular and biochemical changes.