Objective: To evaluate whether cognitive reserve (CR) moderates the relationship between neuropathology and cognitive outcomes after traumatic brain injury (TBI). Setting: Outpatient research organization. Participants: Patients with complicated mild (n = 8), moderate (n = 9), and severe (n = 44) TBI. Design: Prospective, cross-sectional study. Main Measures: Cognitive reserve was estimated using a test of word reading (Wechsler Test of Adult Reading). Diffusion tensor imaging (functional anisotropy) was used to quantify neuropathology. Neuropsychological test scores were submitted to principal components analyses to create cognitive composites for memory, attention, executive function, and processing speed domains. Results: At lower levels of neuropathology, people with higher CR exhibited better memory than those with lower CR. This benefit diminished as neuropathology increased and disappeared at the highest levels of neuropathology. Cognitive reserve ceased exerting a protective effect at premorbid intelligence levels below average. Conclusion: Cognitive reserve may differentially protect some cognitive domains against neuropathology relative to others. A clinical cutoff below which CR is no longer protective, together with a possible neuropathology ceiling effect, may be instructive for prognostication and clinical decision-making in cognitive rehabilitation.