Cognitive reserve could mask the deleterious effects of neurodegenerative disorders in older adults with high premorbid functioning, resulting in false negatives on cognitive screening tests. Failing to detect early signs of cognitive decline may result in missing a critical period of intervention with disease modifying drugs or making informed decisions about end of life issues. The Mini-Mental State Exam (MMSE) and the Dementia Rating Scale, 2nd edition (DRS-2) were compared in a sample of 113 highly educated older adults from northern New England recruited for a research study. Participants were classified as cognitively intact or impaired by a panel of experts based on neuroimaging results, psychometric testing, clinical history, and self-reported level of adaptive functioning corroborated by collateral informants. The 2 instruments produced comparably high specificity, but variable sensitivity to cognitive impairment. Surprisingly, the MMSE consistently outperformed the DRS-2 in overall classification accuracy. Raising the standard cutoffs improved the signal detection performance of both tests with minimal loss in specificity and thus, appears to be a clinically justifiable trade-off. At around 90% specificity, MMSE Ͻ28 and DRS-2 Ͻ139 correctly identified 86% and 67% of the sample. When these cutoffs were restricted to the detection of mild cognitive deficit only, sensitivity declined slightly (81% and 57%, respectively). Neuropsychological tests of memory and executive function were more sensitive to cognitive decline than measures of attention and processing speed. Findings suggest that higher cutoffs may be warranted, and perhaps necessary, in examinees with high educational achievement. At the proposed alternative cutoffs, the MMSE and DRS-2 remained sensitive to even subclinical cognitive deficits. Replication with physician-referred patients is needed to establish the generalizability of the findings to clinical settings.