Little is known about the neuropsychological factors that contribute to individual differences in the asymmetric orientation along the mental number line. The present study documents healthy subjects' preference for small numbers over large numbers in a random number generation task. This preference, referred to as "small-number bias" (SNB), varied with prefrontal functional lateralization: it was larger in participants with over-proportionately better performance in design fluency compared to letter fluency than in participants with over-proportionately better performance in letter fluency when compared to design fluency. Asymmetries in learning and memory tasks (verbal vs. non-verbal) were not related to direction or size of the SNB. We conclude that hemispheric asymmetries of specifically prefrontal executive functions are predictive of an individual's lateral orientation bias along the mental number line. Therefore, the focus on parietal contributions to spatial-numerical associations may not be justified. Random number generation may be a helpful method to further explore these associations uncontaminated by the asymmetric involvement of response effectors.