Background: In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline. Objective: We assessed the association between several measures of body composition and age-related decline in gait speed. Design: Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed-effects models. Results: Gait speed declined by 0.06 +/- 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gait-speed decline (+/-SE) in both men and women (-0.01 +/- 0.00 and -0.02 +/- 0.00 m/s per 0.57 cm(2), respectively; P <0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm(2) increase in thigh intermuscular fat was associated with a 0.01 +/- 0.00-m/s decrease in gait speed, whereas every 16.92-cm(2) decrease in thigh muscle was associated with a 0.01 +/- 0.00-m/s decrease in gait speed. Conclusions: High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed. Am J Clin Nutr 2013;97:552-60.