Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination, adrenal insufficiency, and accumulation of saturated very-long-chain fatty acids (VLFA), particularly hexacosanoate (C26:0). We treated 5 patients with adrenoleukodystrophy (3 males and 2 symptomatic female carriers) for 6 months with a diet enriched in oleic acid (C18:1) and moderately restricted in C26:0. Elevated plasma and erythrocyte levels of C26:0 decreased in a time-dependent manner during treatment. Total plasma C26:0 concentration was lowered by 50 +/- 9% (p less than 0.01); it became normal in the female carriers. The total erythrocyte level of C26:0 decreased (44 +/- 5%; p less than 0.001) into the normal range in all patients. Significant decreases were noted in the saturated VLFA composition of plasma and erythrocyte sphingomyelin and erythrocyte phosphatidylcholine during dietary treatment. In general, decreases in saturated VLFA levels were accompanied by increases in monounsaturated VLFA levels, while total VLFA values did not change. This novel approach to the treatment of adrenoleukodystrophy, in which there is an exchange of monounsaturated VLFA for the more toxic saturated VLFA, may prove clinically beneficial in this disorder.