Agonist-stimulated liberation of arachidonic acid and subsequent generation of active metabolites are established components of several signal transduction pathways including pathways that regulate ion channels. We evaluated the role of arachidonic acid and some related unsaturated and saturated fatty acids in the modulation of a stably expressed recombinant γ-aminobutyric acidA receptor (GABAR) isoform, the α1β2γ2 isoform. Whole-cell currents evoked by 10 µM GABA were inhibited in a concentration-dependent manner by arachidonic acid (0.1–100 µM). This effect of arachidonic acid to inhibit GABAR currents was not reproduced by the non-metabolizable analog of arachidonic acid, 5,8,11,14-eicosatetraynoic acid (ETYA) or by other monounsaturated or saturated fatty acids. However, another polyunsaturated fatty acid, linoleic acid, which is an essential fatty acid and an effective reductant like arachidonic acid, inhibited GABAR currents in a manner similar to arachidonic acid. Nordihydroguaiaretic acid (NDGA), indomethacin and 1-amonibenzotriazole (1-ABT) did not block the inhibitory effect of arachidonic acid, suggesting that arachidonic acid metabolites of the lipoxygenase, cyclooxygenase or P-450 pathways are unlikely to play a major role in the inhibitory effect of arachidonic acid on GABAR currents. However, the antioxidant N-acetyl cysteine (NAC), a scavenger of active oxygen radicals, reduced the inhibitory effect of arachidonic acid on GABAR currents significantly (P<0.01), suggesting that active oxygen radicals might mediate inhibition of GABAR currents by arachidonic acid.