Increases in plasma lipids, tissue triglycerides and decreases in mitochondrial function have been linked to insulin resistance and aging. In animals, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists decrease plasma lipids, intramyocellular fat (IMCL) and liver fat (LFAT) and improve mitochondrial beta-oxidative function and insulin sensitivity, but the effects in elderly were not known. Insulin sensitivity was assessed with a 2-h oral glucose tolerance test, magnetic resonance spectroscopy was used to asses IMCL, LFAT and plasma lipids were measured before and after 6, 11 and 61 days of PPAR-alpha agonist (fenofibrate) administration in 19 elderly (age 70+/-1 years) volunteers. Volunteers were stratified into healthy (N=7) and insulin resistant (N=12) groups. The baseline insulin sensitivity index (8.1+/-1.2 vs. 3.8+/-0.5, healthy vs. insulin resistant; P<0.001) was significantly higher in the healthy group. Fenofibrate treatment induced significant reductions in plasma triglycerides (P<0.001) and total cholesterol (P<0.001) in both groups. Nonetheless, neither fasted free fatty acids, glucose, insulin, nor insulin sensitivity improved in either group (day 1 vs. day 61, 8.1+/-1.2 vs. 8.1+/-0.9, healthy; and 3.8+/-0.5 vs. 4.2+/-0.05, insulin resistant). Furthermore, there was no change in IMCL or LFAT. These results indicate that whereas fenofibrate significantly lowers plasma lipids it neither affects insulin sensitivity nor intracellular lipids in elderly.