We have shown recently that 3,4-methylenedioxymethamphetamine (MDMA) has symptomatic antiparkinsonian activity in rodent models of Parkinson's disease. In search of its mechanism of action, we further investigated the enantiomers of MDMA in the rotational behavioral model and catalepsy test. Catalepsy testing was done in drug-naive unlesioned animals. The parkinsonian symptoms rigor and akinesia (i.e., catalepsy) were induced by intraperitoneal administration of haloperidol 0.5 mg/kg and measured repeatedly as descent latency from a horizontal bar and a vertical grid. MDMA and both its enantiomers were effective in counteracting haloperidol-induced catalepsy, but if given as racemic, the effects were more pronounced than with the enantiomers. For testing of rotational behavior, male Sprague Dawley rats were lesioned unilaterally with 6-hydroxydopamine (6-OHDA) at the medial forebrain bundle. Administration of S-MDMA (5 mg/kg) produced ipsilateral rotations. R-MDMA was far less effective in inducing ipsilateral rotations in 6-OHDA unilaterally lesioned rats, but when S-MDMA was given additionally rotations immediately increased. Regarding their overall antiparkinsonian effects, the S-enantiomer of MDMA was more effective than its R-congener. R-MDMA was able to increase the actions of S-MDMA. Synapse 55:148–155, 2005. © 2004 Wiley-Liss, Inc.