We examined lifespan changes in five domains of cognitive performance as predictive of mortality risk. Data came from the Manchester Longitudinal Study of Cognition, a 20-plus year investigation of 6203 individuals aged 42–97 years. Cognitive domains included crystallized intelligence, fluid intelligence, verbal memory, visual memory, and processing speed. Lifespan decrements were evident across these domains, controlling for baseline performance at age 70 and adjusting for retest effects. Survival analyses stratified by sex and conducted independently by cognitive domain showed that lower baseline performance levels in all domains—and larger lifespan decrements in fluid intelligence and processing speed—were predictive of increased mortality risk for both females and males. Critically, analyses of the combined predictive power of cognitive performance variables showed that baseline levels of processing speed (in females) and fluid intelligence (in males), and decrements in processing speed (in females and in males) and fluid intelligence (in females), accounted for most of the explained variation in mortality risk. In light of recent evidence from brain imaging studies, we speculate that cognitive abilities closely linked to cerebral white matter integrity (such as processing speed and fluid intelligence) may represent particularly sensitive markers of mortality risk. Additionally, we presume that greater complexity in cognition-survival associations observed in females (in analyses incorporating all cognitive predictors) may be a consequence of longer and more variable cognitive declines in females relative to males.