<p>This study examined the cross-sectional and longitudinal associations between neighborhood socioeconomic disadvantage and frailty in middle-to-older-aged adults. Data were obtained from a cohort study conducted in Brisbane, Australia, with 3966 participants (mean age 58.2&#xa0;years; female 57.6%) included in cross-sectional analysis and 2846 in longitudinal analysis (3-year follow-up). A frailty index (FI), a composite score consisting of 32 items, was used continuously (range 0–1) and categorized into frail (FI &gt; 0.35) and non-frail. Neighborhood disadvantage was measured using the Index of Relative Socioeconomic Disadvantage, an area-level composite index, and was categorized into tertiles. Two-level mixed-effects linear and logistic regression models were fitted, accounting for area-level clustering through random intercepts for areas and adjusting for demographic variables and individual-level socioeconomic status. In the cross-sectional analysis, 11% of participants were frail. Compared to residents of low disadvantage neighborhoods, those in middle and high disadvantage neighborhoods had higher levels of frailty and greater odds of being frail (OR = 1.54 [95% CI 1.13, 2.09] and OR = 2.86 [2.11, 3.88], respectively). In the longitudinal analysis, residing in middle and high disadvantage neighborhoods was significantly associated with increases in FI scores, relative to low disadvantage neighborhoods. Incident frailty was observed in 5% of participants at the follow-up. Residing in high disadvantage neighborhoods showed significantly higher odds of incident frailty (OR = 1.75 [1.08, 2.86]). Mid-to-older-aged residents of disadvantaged neighborhoods are more likely to be frail and to become frail over 3 years, compared to those in advantaged neighborhoods. Community-level interventions to reduce frailty should target disadvantage neighborhoods.</p>