OBJECTIVE: Though polyunsaturated fatty acids (PUFA) reduce seizures in several animal models, results have been inconsistent in humans. The goal of the present study was to assess the effectiveness of a PUFA supplement as adjunctive treatment for intractable focal or generalized epilepsy in humans. METHODS: Adults with uncontrolled epilepsy were randomized to either mineral oil placebo or a PUFA supplement (eicosapentanoic acid (EPA) plus docosahexanoic acid (DHA), 2.2 mg/day in a 3:2 ratio). Following a 4-week prospective baseline and 1-week titration, subjects entered a 12-week treatment period, followed by an optional 4-week open-label phase. RESULTS: Of 21 subjects (12 PUFA and 9 placebo), 0 on PUFA versus 2 on placebo had at least a 50% decrease in seizure frequency from baseline (P=0.17). Overall, seizure frequency increased 6% on PUFA and decreased 12% on placebo (P=0.21). During optional open-label administration, however, 15 of 19 subjects had fewer seizures than during baseline (P=0.02). CONCLUSIONS: Based on the randomized, blinded portion of this study, the PUFA preparation used was not superior to placebo as adjunctive treatment for intractable epilepsy. It is not known whether different doses or different EPA:DHA ratios would be effective.