Considering the implication of vascular and metabolic disruption in the pathogenesis and progression of diabetic neuropathy (DN), we investigated the effects of a combination of prostaglandin (PG) E1 analogue, OP 1206·α CD (OP), and aldose reductase inhibitor (ARI), ICI 128436 (ICI), on the polyneuropathy in long-term streptozocin (STZ)-induced diabetic (DM) rats. DM rats were treated daily with OP alone (10μg/kg/day), OP (10μg/kg/day) and ICI (35mg/kg/day), or saline by gastric gavage for 2months, heginning 5 months after induction of diabetes. Age-matched non-DM rats were treated with saline in the same manner, as controls. Body weight reduction and hyperglycemia of DM rats were unchanged throughout the experiment irrespective of treatment. The reduction in sciatic motor nerve conduction velocity in DM rats (49.8±2.1m/s), p<0.01 vs control (57.6±1.4) was significantly improved at the end of the experiment with OP (53.2±1.7, p<0.05 vs untreated DM), and was normalized by treatment with the combination of OP and ICI (55.9±1.7, p<0.01 vs untreated DM). Sciatic sorbitol accumulation and myo-inositol depletion in DM rats were improved only by the combined regimen. Impaired sciatic Na+, K+-ATPase activity in DM rats, moreover, was restored to the control level with this regimen. These results suggest that (1) a combination of PGEi and ARI may be more effectivefor neuropathy in long-term STZ-DM rats, (2) both vascular and metabolic disruptions may be implicated in the progression of DN, and (3) this combination therapy should be considered for the treatment of human DN.