Objectives: One-third of epileptic patients are resistant to antiepileptic drugs. Few clinical studies with small sample size indicate that polyunsaturated fatty acids could control drug-resistant epilepsy. We examined the efficacy of acute and chronic administration of docosahexaenoic acid (DHA) in two animal models of drug-resistant epilepsies, i.e. 6-Hz psychomotor seizures in mice and lamotrigine (LTG)-resistant kindled rats. Methods: Mice received a single injection of DHA (300 µM, i.c.v.) along with phenytoin (PHT) or LTG (i.p.). Six-Hz electroshock (0.2 milliseconds rectangular pulse width, 3 seconds duration, 44 mA current) was given 15 minutes after DHA, and seizure behaviors were recorded. In LTG-resistant kindled rats, a single dose of DHA (300 µM, i.c.v.) was administered with LTG, and seizure parameters were measured. In chronic treatment, mice received DHA (0.1 g/day, orally) for 30 days. Then, a single dose of LTG or PHT was administered to mice and 6-Hz-induced seizures were recorded. In rats, DHA (1 µM, i.c.v.) was administered during kindling development and effect of LTG in DHA-pretreated LTG-resistant kindled rats was verified. Results: LTG and PHT did not inhibit 6-Hz seizures in mice after single injection of DHA. However, LTG and PHT inhibited 6-Hz seizures in mice that received DHA for 1 month. Acute or chronic administration of DHA to LTG-resistant kindled rats led to the suppression of kindled seizure parameters by LTG. Discussion: DHA removes the 'inherent resistance' of 6-Hz seizures to PHT and LTG, and prevents the development of pharmacodynamic tolerance to LTG in LTG-resistant kindled rats. DHA might have potential to be used as add-on therapy in patients with refractory epilepsy.