The purpose of this study was to examine age-related differences in the magnitude of caffeine-induced thermogenesis and the relationship of aerobic fitness, body composition, and hormone and substrate concentrations to the thermic effect of caffeine in younger and older women. Using a placebo-controlled, double-blind study design, 10 older (50 to 67 years) and 10 younger (21 to 31 years) healthy women who were moderate consumers of caffeine (self-reported intake: younger, 139 +/- 152 mg/d; older, 204 +/- 101 mg/d, NS, mean +/- SD) were characterized for fasting plasma glucose, insulin, free fatty acid (FFA), and caffeine levels, energy expenditure, body composition, anthropometry, aerobic fitness, physical activity, and energy intake. Before and after placebo and caffeine ingestion (5 mg/kg fat-free mass [FFM]), the following variables were measured: fasting plasma glucose, insulin, FFA, and energy expenditure, plasma glucose, insulin, and FFA, and energy expenditure in response to placebo and caffeine ingestion. Caffeine ingestion resulted in similar increases in younger and older women for plasma caffeine (younger, 80 +/- 34 to 5,604 +/- 528 ng/mL, P < .01; older, 154 +/- 134 to 5,971 +/- 867 ng/mL, P < .01) and fatty acids (younger, 294 +/- 118 to 798 +/- 248 micromol/L, P < .01; older, 360 +/- 180 to 727 +/- 310 micromol/L, P < .01), whereas plasma insulin and glucose levels remained unchanged from baseline. Energy expenditure increased following caffeine ingestion in both groups (younger, 15.4%, 1.09 +/- 0.14 to 1.24 +/- 0.13 kcal/min, P < .05; older, 7.8%, 0.98 +/- 0.14 to 1.06 +/- 0.12 kcal/min, P < .05), although there was a blunted thermic response in the older versus younger women (older, 6.9 +/- 5 kcal/90 min; younger, 15.5 +/- 7 kcal/90 min, P < .05). In younger women, the thermic response to caffeine was positively correlated with the waist circumference (r = .70, P < .05) and body weight (r = .91; P < .01), whereas aerobic fitness (r = .77; P < .05) was the only significant correlate in older women. In conclusion, older and younger women increase energy expenditure significantly following caffeine ingestion, but older women have a blunted thermic response compared with younger women. Second, the thermic response to caffeine is positively associated with the body weight and waist circumference in younger women, whereas a positive association with aerobic fitness was observed in older women. Thus, the physiologic determinants of the thermic response to caffeine differ among women of different age groups.