The nature of histamine receptors in peripheral tissues is still controversial. However, evidence of heterogeneous classes of binding sites for [³H]-mepyramine are reported in the literature. The aim of our study was, therefore, to investigate the nature of this heterogeneity by comparing [³H]-mepyramine study was, therefore, to investigate the nature of this heterogeneity by comparing [³H]-mepyramine binding in a central tissue (cerebellum) and in a peripheral tissue (lung) obtained from guinea pigs and to assess its dependence upon the temperature of incubation. The results revealed that the [³H]-mepyramine interaction in both tissues is temperature-dependent. At 25°C, the interaction between [³H]-mepyramine and the receptors was biphasic in the lung while only a single class of binding site was found in the cerebellum. At 0°C, [³H]-mepyramine interacted with three binding sites in the lung and two in the cerebellum. The behaviour of the reference compounds (clemastine, promethazine and histamine) also supported this temperature-dependence. Moreover, two new compounds (DF 11062 and DF 11113), synthesized in our laboratories and endowed with antihistamine activity, can differentiate between the low affinity site seen at 25°C in the lung and that seen in the cerebellum at 0°C.