Rotenone-induced parkinsonism in rats is a widely used animal model of parkinsonism for studies of the antiparkinsonism activity of new substances. The guanidine derivatives of adamantane 1-adamantylguanidine hydrochloride (IEM-2151) and 3,5-dimethyl-1-adamantylguanidine hydrochloride (IEM-2163) given p.o. at a dose of 10 mg/kg had signifi cantly greater antiparkinsonism effects than levodopa at a dose of 20 mg/kg and memantine at a dose of 5 mg/kg, as they reduced the proportion of rats with severe oligokinesia 1.5–3 times more effectively than memantine and levodopa and, in contrast to memantine and levodopa, completely eliminated severe catalepsy in rats with rotenone-induced parkinsonism. IEM-2151 was the safest substance, as it prevented lethality among rats throughout the experiment, while memantine and levodopa increased lethality among the animals towards the end of the experiment. Combined p.o. administration of levodopa with IEM-2151 at the low doses of 10 and 5 mg/kg, respectively, produced a maximal synergistic antiparkinsonism effect, which was greater than the effects of each drug alone at twice the dose. The combination of IEM-2151 with levodopa at low therapeutic doses is a potentially effective and safe approach to the treatment of levodopa-refractory parkinsonism.