OBJECTIVES: To test whether accelerated sarcopenia in older persons with high interleukin (IL)-6 serum levels plays a role in the prospective association between inflammation and disability found in many studies. DESIGN: Cohort study of older women with moderate to severe disability. PARTICIPANTS: Six hundred twenty older women from the Women's Health and Aging Study in whom information on baseline IL-6 serum level was available. MEASUREMENTS: Self-report of functional status, objective measures of walking performance, and knee extensor strength were assessed at baseline and over six semiannual follow-up visits. Potential confounders were baseline age, race, body mass index, smoking, depression, and medical conditions. RESULTS: At baseline, women with high IL-6 were more often disabled and had lower walking speed. After adjusting for confounders, women in the highest IL-6 tertile (IL-6 >3.10 pg/mL) were at higher risk of developing incident mobility disability (risk ratio (RR) = 1.50, 95% confidence interval (CI) = 1.01-2.27), disability in activities of daily living (RR = 1.41, 95% CI = 1.01-1.98), and severe limitation in walking (RR = 1.61, 95% CI = 1.09-2.38) and experienced steeper declines in walking speed (P < .001) than women in the lowest IL-6 tertile (IL-6 ≤1.78 pg/mL). Decline in knee extensor strength was also steeper, but differences across IL-6 tertiles were not significant. After adjusting for change over time in knee extensor strength, the association between high IL-6 and accelerated decline of physical function was no longer statistically significant. CONCLUSIONS: Older women with high IL-6 serum levels have a higher risk of developing physical disability and experience a steeper decline in walking ability than those with lower levels, which are partially explained by a parallel decline in muscle strength.