The objective of this study was to determine the association of seizures and cognitive decline in adults with Down syndrome (DS) and Alzheimer's-type dementia. A retrospective data analysis was carried out following a controlled study of antioxidant supplementation for dementia in DS. Observations were made at baseline and every 6 months for 2 years. Seizure history was obtained from study records. The primary outcome measures comprised the performance-based Severe Impairment Battery (SIB) and Brief Praxis Test (BPT). Secondary outcome measures comprised the informant-based Dementia Questionnaire for Mentally Retarded Persons and Vineland Adaptive Behavior Scales. Because a large proportion of patients with seizures had such severe cognitive decline as to become untestable on the performance measures, time to "first inability to test" was measured. Adjustments were made for the potentially confounding co-variates of age, gender, APOE4 status, baseline cognitive impairment, years since dementia onset at baseline, and treatment assignment. The estimated odds ratio for the time to "first inability to test" on SIB comparing those with seizures to those without is 11.02 (95% CI: 1.59, 76.27), a ratio that is significantly different from 1 (p = 0.015). Similarly, we estimated an odds ratio of 9.02 (95% CI: 1.90, 42.85) on BPT, a ratio also significantly different than 1 (p = 0.006). Results from a secondary analysis of the informant measures showed significant decline related to seizures. We conclude that there is a strong association of seizures with cognitive decline in demented individuals with DS. Prospective studies exploring this relationship in DS are indicated.