Background Loxapine is a typical antipsychotic while isoloxapine, its 8Cl-isomer, shows atypicality in some animal models. The basis for this difference is not well understood. The purpose of this study was to systematically compare the two drugs in in vitro and in vivo animal models, and to understand mechanisms underlying their differential typical/atypical profiles. Methods The in vitro and in vivo receptor profiles as well as the action of loxapine and isoloxapine on rat conditioned avoidance response (CAR), catalepsy (CAT), striatal FOS expression and prolactin levels were determined. To understand loxapine's typical profile, we added MDL100,907, to provide loxapine + MDL the same in vivo 5-HT 2 / D 2 ratio as isoloxapine, while holding its D 2 component constant. Results Isoloxapine behaved as an “atypical” antipsychotic demonstrating CAR inhibition, low CAT, no significant prolactin elevation, and minimal FOS expression in the dorsolateral striatum. Loxapine behaved like a typical antipsychotic, showing unexpectedly high in vivo D 2 occupancy. Addition of MDL100,907, which resulted in a very high 5-HT 2 / D 2 in vivo ratio, did not alter loxapine + MDL's typical profile. Conclusions Loxapine's behaviour as a typical antipsychotic is most likely due to its disproportionately high D 2 occupancy. Appropriate action at D 2 receptors in vivo, rather than the high 5-HT 2 / D 2 ratio, seems to be critical in determining why isoloxapine behaves like an atypical antipsychotic.