Thiomersal (thimerosal) was a weak inhibitor of the binding of [(3)H]mepyramine to histamine H(1) receptors in guinea-pig cerebellar membranes (11 +/- 1% inhibition at 10 microM, 32 +/- 3% inhibition at 300 microM). However, in the concentration range 3-30 microM, thiomersal enhanced the binding of histamine to the H(1) receptor, as reflected by the displacement of curves of histamine inhibition of [(3)H]mepyramine binding to lower concentrations, without any change in the Hill coefficient. The ratio of the IC50 values (the concentration giving 50% inhibition) in the absence and presence of thiomersal increased from 1.8 with 3 microM to 3.6 with 30 microM thiomersal. There was no consistent effect of thiomersal at concentrations of 30 microM and below on curves of mepyramine inhibition of [(3)H]mepyramine binding. In the presence of 10 microM thiomersal histamine-induced accumulation of inositol phosphates in U373 MG astrocytoma cells was partially inhibited (37 +/- 8% inhibition of the maximum response), without any significant change in the EC50 (the concentration giving the half maximal response) for histamine. Thus although histamine binding was potentiated by thiomersal, there was no potentiation of an H(1) receptor-mediated functional response.