The transmembrane energy-dependent efflux transporter P-glycoprotein (P-gp) limits a range of drugs from penetrating cells and deposits them into the extracellular space. P-gp is highly expressed in several normal tissues, including the luminal surface of capillary endothelial cells in the brain of humans. In this study, we tested whether olanzapine distribution to tissues highly expressing P-gp or devoid of this transporter was similar in Abcb1a (-/-) mice lacking P-gp and control animals. At 1 h following the intraperitoneal injection of 2.5 microg olanzapine/g mouse, olanzapine concentrations were statistically and significantly higher in brain (three-fold), liver (2.6-fold), and kidney (1.8-fold) of Abcb1a (-/-) mice than those of the control FVB Abcb1a (+/+) mice, and not statistically different in plasma, spleen, or penile tissue. Similar differences were also found for the ratios of organ:plasma and organ:spleen between the two groups. This is the first report that the presence of the Abcb1a gene is an important factor controlling brain access to olanzapine. The finding that the brain penetration of olanzapine is limited by P-gp implies that the highly prevalent functional polymorphisms of ABCB1 in humans may be a factor contributing to variability in dose requirements for this antipsychotic drug.