Essential fatty acid metabolism is impaired by diabetes mellitus and gamma-linolenic acid rich treatments such as evening primrose oil correct deficits in nerve conduction and endoneurial blood flow in diabetic rats. Other mechanistically unrelated treatments, such as antioxidants and aldose reductase inhibitors have a similar effect and there may be positive interactions with multiple treatments. Our aim was to compare the efficacy of a novel essential fatty acid derivative, ascorbyl gamma-linolenic acid, with that of gamma-linolenic acid in correcting diabetic neurovascular deficits. Eight weeks of diabetes caused 20.4 and 48.2% reductions in sciatic motor conduction velocity and nutritive endoneurial blood flow, respectively. Treatment was given for the last 2 weeks with gamma-linolenic acid (100 mg.kg-1.day-1) either in pure form or as ascorbyl gamma-linolenic acid, an equivalent dose of ascorbate (21 mg.kg-1.day-1) or jointly with ascorbate and gamma-linolenic acid. Conduction velocity was corrected by 39.8, 87.4, 13.2 and 66.8% with gamma-linolenic acid, ascorbyl gamma-linolenic acid, ascorbate and gamma-linolenic acid plus ascorbate, respectively. Corresponding ameliorations of the nutritive blood flow deficit were 44.0, 87.4, 87.4, 13.2 and 65.7%. For the gamma-linolenic acid plus ascorbate combinatin, and especially for ascorbyl gamma-linolenic acid, the magnitude of correction for conduction velocity and blood flow was greater than expected for simple addition of ascorbate and gamma-linolenic acid, indicating a synergistic interaction. Thus, with an efficacy 40 times that of evening primrose oil in rats, ascorbyl gamma-linolenic acid may be a suitable candidate for clinical trials of diabetic neuropathy.