OBJECTIVE: The brain reserve hypothesis was examined in a secondary analysis of cross-sectional data from a community-based sample of 468 older adults residing in Charlotte County, Florida. The objective of the analysis was to determine the association between head circumference and eight cognitive outcomes and to assess any potential effect modification of existing associations by Apolipoprotein E (APOE) genotype. METHODS: Cognitive outcomes include scores from the Modified Mini-Mental State Exam (3MS), the Hopkins Verbal Learning Test-Revised (HVLT-R), Stroop Color-Word Test, Trail-Making Test A and B, and a word-stem completion task measuring implicit memory. Descriptive statistics were calculated for each variable. Head circumference and dependent cognitive outcomes were modeled as dichotomous variables using logistic regression, adjusting for gender, age, education, income, height, and Spot The Word test score, a measure of pre-morbid IQ. For dichotomized test scores, poor outcomes (cases) were defined as having scores in the lowest quintile; the remaining top four quintiles were considered non-cases. RESULTS: small head circumference was significantly associated with low 3MS scores [OR(95%CI): 2.97 (1.12, 7.89), p=0.03], after adjustment for age, income and pre-morbid IQ. The association remained statistically significant after adjustment for gender and education as well. After adjustment, head circumference was not found to be statistically significantly associated with any other cognitive outcome. No effect modification was found by APOE genotype or years of education. CONCLUSION: This analysis confirms previous findings that exposure to low head circumference significantly impacts cognition in late life.