Factors influencing the behavioral sensitization ("reverse tolerance") produced by intermittent amphetamine (AMPH) injections were studied by quantifying rotational behavior in rats that had a unilateral 6-hydroxy-dopamine lesion of the substantia nigra. The results indicate that: a single injection of a low dose of AMPH enhances rotational behavior induced by a second injection of AMPH for up to 12 weeks; multiple, weekly injections of AMPH produce a progressive enhancement in rotational behavior, over-and-above that produced by a single injection; female rats show more robust sensitization than males following single or multiple injections of AMPH; this sex difference may be due to the suppression of sensitization by an androgen, because removal of testicular hormones potentiates sensitization; the long-lasting sensitization of rotational behavior produced by infrequent injections of AMPH is not due to drug-environment conditioning effects, but perhaps to a persistent AMPH-induced change(s) in brain catecholamine systems; and a simple change in DA receptors is probably not involved, because the sensitization produced by infrequent injections of AMPH does not influence the rotation produced by a subsequent injection of apomorphine. The results illustrate an intriguing example of neuroplasticity that may have clinical relevance.