A detailed computational study on a series of 4-quinolinecarbinolamine antimalarials was performed using the semiempirical Austin model 1 (AM1) quantum chemical method to correlate the electronic features with antimalarial activity and to illuminate more completely the fundamental molecular level forces that affect the function and utility of the compounds. Ab initio (3-21G level) calculations were performed on mefloquine, the lead compound in this series, to check the reliability of the AM1 method. Electron density in specific regions of the molecules appears to play the pivotal role toward activity. A large laterally extended negative potential in the frontal portion of the nitrogen atom of the quinoline ring and the absence of negative potential over the molecular plane are crucial for the potent antimalarials. These electrostatic features are likely to be the modulator of hydrophobicity or lipophilicity of the compounds and, hence, determine their activities. The magnitude of the positive potential located by the hydroxyl hydrogen atom also correlates with potent antimalarial activity. Two negative potential regions occur near the hydroxyl oxygen and piperidyl nitrogen atoms. The two negative potential regions and the positive potential located by the hydroxyl hydrogen atom are consistent with intermolecular hydrogen bonding with the cellular effectors. The present modeling study should aid in efficient designing of this class of antimalarial agents.