Among the compounds endowed with the capacity to reverse the P-glycoprotein (Pgp)-mediated multidrug resistance of cancer cells, a powerful agent was found to be the cyclosporin D derivative SDZ PSC 833. After in vivo treatment with SDZ PSC 833, mice showed a decreased tolerability to cyclosporin A (CsA), but also to ivermectin, a widely used polycyclic lactone pesticide of Streptomyces avermitills origin. The sequels were suggestive of CsA- or ivermectin-induced central nervous system dysfunction; they were interpreted as caused by the neutralization of the Pgp at the blood-brain barrier level, implying that CsA and ivermectin were Pgp substrates. CsA was already known to display both Pgp substrate and Pgp inhibitor properties. It now appears that ivermectin may also inhibit Pgp function. When compared in short-term assays for Pgp function inhibition, which measure the restoration of the retention of two Pgp probes in multidrug-resistant (MDR) cells to their parental (Par) cell levels, ivermectin appeared only a few fold weaker than SDZ PSC 833 in the case of murine monocytic leukemia MDR-P388 cells and nearly as active as SDZ PSC 833 in the case of human lymphocytic leukemia MDR-CEM cells. Therefore, like CsA or FK-506, ivermectin may be both a substrate and an inhibitor of Pgp.