OBJECTIVE: To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB), in healthy older individuals. DESIGN: Cross-sectional clinical study. SETTING: Berkeley, California. PARTICIPANTS: Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011. MAIN OUTCOME MEASURES: Cortical [(11)C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise. RESULTS: Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [(11)C]PiB uptake (P < .001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [(11)C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [(11)C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [(11)C]PiB uptake. CONCLUSIONS: Individuals with greater early- and middle- life cognitive activity had lower [(11)C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [(11)C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.