Abstract Symptoms of major depressive disorder (MDD) manifest variably across individuals. Accordingly, recent models of the disorder imply that MDD may be characterized according to independent symptom dimensions. In particular, several studies reveal that depression may be characterized along dimensions of negative affect, agitation and hostility, and lassitude and malaise. No research has examined the relationship between these dimensions and neuropsychological function. Towards this end, 133 in patients with unipolar MDD and 17 people without psychiatric illness were administered a brief battery of neuropsychological tests and the MMPI-2. Paralleling earlier research, principal component analysis of the MMPI-2 revealed symptom dimensions of negative affect, agitation, and lassitude and malaise. Multiple regression analyses showed that the negative affect and agitation dimensions accounted for significant variance on measures of executive function, speed of information processing, new learning, dexterity, and overall impairment. Lassitude and malaise failed to correspond with neuropsychological performance. Implications of these data for clinical practice and neural models of MDD are discussed.