The most effective antimalarial agents among the N4-monosubstituted 2-acetylpyridine thiosemicarbazones recently described by us have a cyclohexyl or a phenyl substituent and produce cures in Plasmodium berghei infected mice at a dose of 160 and 320 mg/kg, respectively. We report here on a related series of N4,N4-disubstituted 2-acetylpyridine thiosemicarbazones. Several members of this group bearing alkyl or cycloalkyl substituents at N4 show activity superior to the most active monosubstituted 2-acetylpyridine thiosemicarbazones. However, the greatest improvement in potency was seen when the N4-nitrogen atom was incorporated into a six- or seven-membered ring, such as the piperidine, piperazine, or azabicyclo[3.2.2]nonane systems, to give compounds with curative properties at a dose level as low as 20 mg/kg.