It has been proposed that the arylalkylamine, (-)pindolol, potentiates the therapeutic action of antidepressant drugs in humans by blockade of 5-HT1A autoreceptors. Its interactions at human 5-HT1A receptors have not, however, been directly characterized. Herein, we demonstrate that (-)pindolol exhibits nanomolar affinity at human 5-HT1A receptors expressed in Chinese Hamster Ovary cells (CHO-h5-HT1A; Ki = 6.4 nmol/L). In a functional test of receptor-mediated G-protein activation (stimulation of [35S]-GTP gamma S binding) (-)pindolol displays an efficacy of 20.3% relative to the endogenous agonist, 5-HT (= 100%). (-)Pindolol also antagonizes 5-HT (100 nmol/L)-stimulated [35S]-GTP gamma S binding, reducing it to 19.8% of control binding. These data indicate that (-)pindolol acts as a (weak) partial agonist at CHO-h5-HT1A receptors and that it blocks the action of 5-HT at these sites.