Background: Inflammation is implicated in functional decline and the development of disability in aging. This study aimed to investigate the association of inflammation with physical function and muscle strength in older adults with obesity and increased cardiometabolic risk. Design: In baseline assessments from the CROSSROADS randomized controlled trial, serum interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and C-reactive protein (hs-CRP) were assayed in 163 older adults (37% males, 24% African American, BMI 34±3, age 70±5yrs) with hypertension, dyslipidemia and/or diabetes. Physical function was assessed by sixminute walk test (6MWT), chair sit-and-reach (CSR), hand-grip and knee-extension strength; specific-strength as muscle strength/mass ratio. Analyses included ANCOVA and multiple linear regression adjusted for thigh skeletal muscle (MRI), arm lean mass (DXA) and moderate-to-vigorous intensity physical activity (MVPA; accelerometry). Results: Higher hs-CRP (p<0.01) and IL-6 (p=0.07) were associated with lower 6MWT and CSR, respectively. A composite inflammation score combining all 3 inflammatory markers showed the strongest inverse association with 6MWT (p<0.01). MVPA moderated associations such that amongst participants who engaged in low MVPA, 6MWT distances and CSR scores were significantly lower in those with high IL-6 and TNFα (p<0.05), respectively. In participants with high MVPA, higher hs-CRP (p<0.05) and TNFα (p=0.07) were associated with poorer upper-extremity specific-strength. Conclusions: Chronic inflammation was associated with poorer physical function and specific strength in older adults with obesity and increased cardiometabolic risk. This association was strongest in participants with multiple elevated inflammatory markers. Physical activity levels below current recommendations mitigated the deleterious effects of inflammation on lower body mobility, underscoring the benefits of exercise for preserving physical function with age.