Rats were trained to discriminate i.p. injections of mepyramine (10.0 mg/kg) from saline. Correct responses on one of the two levers were reinforced with access to a solution of sweetened condensed milk. A level of at least 27 correct responses in the first 30 (90%) was required in consecutive saline and mepyramine training sessions before a test session was conducted. Amongst the antihistamines, mepyramine, tripelennamine and chlorpheniramine all produced dose-related responding on the mepyramine lever, reaching a maximum of over 90% mepyramine-appropriate responses. Both tripelennamine and chlorpheniramine were more potent than the training drug. Diphenhydramine and promethazine produced high levels of mepyramine-appropriate responses, but the 90% level was not reached with any dose tested. The dextrorotatory isomer of chlorpheniramine, which binds with high affinity to H1-receptors, was approximately twice as potent as the racemic mixture. The anticholinergic, scopolamine, and the local anaesthetic, procaine, produced only low levels of mepyramine-appropriate responses. However, 10.0 mg/kg of the anti-depressant imipramine produced over 90% mepyramine-appropriate responses. These results suggest that a discrimination can be formed on the basis of the specific H1-receptor antagonist activity of mepyramine.