A substantial disturbance of the metabolism of the n-6 essential fatty acids (EFAs) exists in both human and experimental diabetes mellitus. The process of conversion of dietary linoleic acid to gammalinolenic, dihomogammalinolenic and arachidonic acids, and other polyunsaturates is inadequate in diabetic patients. Disturbances of these EFAs and the 1- and 2-series prostaglandins derived from them cause a variety of microvascular, haemorheological, and other abnormalities leading to reduced blood flow and neural hypoxia. This will in turn produce an escalating cycle of further hypoxia through the generation of oxygen-free radicals and aggravation of neural capillary endothelial damage. Endoneurial hypoxia impairs axonal transport, produces demyelination, and reduces neural ATP-ase activity. Furthermore, depletion of polyunsaturated fatty acids derived from n-6 pathway may lead to abnormalities of myelin turnover, membrane-bound proteins (such as enzymes and receptors) and other axonal structural abnormalities. The disorders postulated here may synergistically interact with the metabolic changes described in both the glycosylation and the myoinositol hypotheses and may have important implications in the approach to treat diabetic neuropathy.