The association between high-sensitivity -reactive protein (hsCRP) and activities of daily living (ADL) disability remains unclear. Our study aimed to comprehensively explore the relationship between hsCRP concentrations and the risk of ADL disability, while also identifying potential modifiers of this association in middle-aged and older adults. We conducted a prospective study involving 16,342 participants aged 50 years and older (mean age: 64 ± 10 years) from the Health and Retirement Study. To investigate the longitudinal association between hsCRP and the risk of ADL disability, we employed Cox proportional hazard regression models, adjusting for a wide range of potential confounders. Subgroups analyses were further conducted to examine interactions across factors such as gender, age, body mass index, smoking status, and drinking status. This study involved a follow-up of 125,858 person-years (median of 8 years; interquartile range: 4-12 years), revealing a total of 4579 incidents of ADL disability. The highest hsCRP concentration was significantly associated with ADL disability after adjustment for covariates (hazard ratio [HR] = 1.25; confidence interval [CI] = 1.14-1.36). The associations between hsCRP and the risk of ADL disability seemed to be somewhat stronger among individuals aged < 65 years and with a BMI ≥ 30 kg/m (both for interaction < 0.05). Our findings indicated that elevated hsCRP concentrations are associated with an increased risk of ADL disability in middle-aged and older adults. HsCRP appears to serve as a biomarker for ADL disability, particularly among individuals with obesity and middle-aged adults.