BACKGROUND: The Medical Outcomes Study Questionnaire Short Form 36 health survey (SF-36) measures health-related quality of life (HRQoL) from the individual's point of view and is an indicator of overall health status. OBJECTIVE: To examine whether HRQoL shows differential changes over time prior to dementia onset and investigate whether HRQoL predicts incidence of dementia. DESIGN: Prevention of Alzheimer's Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non-demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis. SETTING: Secondary data analysis of PREADViSE data. PARTICIPANTS: A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis. MEASUREMENTS: Two summary T scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean of 50 (standard deviation of 10); higher scores are better. Linear mixed models (LMM) were applied to determine if mean component scores varied over time or by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline component scores were associated with dementia incidence, adjusting for baseline age, race, APOE-4 carrier status, sleep apnea, and self-reported memory complaint at baseline. RESULTS: The mean baseline MCS score for participants who later developed dementia (mean± SD: 53.9±9.5) was significantly lower than for those participants who did not develop dementia during the study (mean±SD: 56.4±6.5; p = 0.005). Mean PCS scores at baseline (dementia: 49.3±7.9 vs. non-dementia: 49.8±7.8) were not significantly different (p = 0.5) but LMM analysis showed a significant time effect. For MCS, the indicator for eventual dementia diagnosis was significantly associated with poorer scores after adjusting for baseline age, race, and memory complaint. Adjusted for other baseline risk factors, the Cox model showed that a 10-unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%-55%). CONCLUSION: The SF-36 MCS summary score may serve as a predictor for future dementia and could be prognostic in longitudinal dementia research.