The benzothiazepine, diltiazem, is commonly used as an inhibitor of vascular L-type Ca channels, and is a clinically important anti-anginal and antihypertensive medication. In the retina, diltiazem also inhibits cyclic-nucleotide gated (CNG) channels, including the cGMP-gated channels in photoreceptors, and has been suggested to be a neuroprotectant in an animal model of retinitis pigmentosa, a degenerative disease of photoreceptors. In contrast to CNG channels, the actions of diltiazem on photoreceptor Ca channels have not been studied. We show that D-cis-diltiazem can block Ca channels in cone photoreceptors and that the potency and efficacy of cone photoreceptor Ca channel inhibition by this drug is unconventional. Over the concentration range of 5-500 microM diltiazem, the dose response curve was biphasic with a high affinity saturation level of approximately 30% block in the 20-50 microM range (IC(50)=4.9 microM) and a low affinity saturation block (near 100%) with concentrations up to 500 microM (IC(50)=100.4 microM). The degree of block was found to be equivalent when Bay K 8644 was used to increase Ca channel current, indicating that the levels of block do not result from multiple Ca channel subtypes having differing sensitivities to diltiazem. Calcium imaging showed that the relatively low efficacy of the high-affinity Ca channel block was not due to the species of charge-carrying divalent cation nor that it was associated with dialysis of cellular contents. These data contribute to an emerging perspective that the photoreceptor Ca channel has properties unique from other L-type channels, an important consideration should these channels become a target for testing putative neuroprotective therapies.