Plasma and CSF gamma-aminobutyric acid (GABA) levels were determined in patients with affective illness and normal volunteers. Plasma GABA was significantly lower in the medication-free euthymic bipolar group (n = 23, p = 0.03) compared to normal volunteers (n = 36). Lithium-treated euthymic bipolar patients (n = 26) tended to have higher plasma GABA levels (p = 0.09) than the medication-free euthymic bipolar group. Plasma GABA in nine patients, measured in the euthymic state on and off lithium, was higher during lithium treatment (p less than 0.02). In CSF, GABA was found to be significantly lower in a group of euthymic medication-free unipolar and bipolar patients (n = 9) compared to normal volunteers (n = 39, p less than 0.02). CSF GABA, on and off lithium in four bipolar patients, was significantly higher during lithium treatment (p less than 0.02). This effect of lithium, increasing CSF and plasma GABA, may be related to its mechanism of therapeutic action.