Cholesterol lowering drugs are associated with myopathic side effects in 7% of those on therapy, which is reversible in most, but not all patients. This study tested the hypothesis that total body fat oxidation (TBFO) is reduced by statins in patients with genetic deficiencies in FO, determined by white blood cells (FOwbc) and by molecular analysis of common deficiencies, and would cause intolerance in some patients. Six patients on statin therapy without myopathic side effects (tolerant) and 7 patients who had previously developed statin-induced myopathic symptoms (intolerant) (age=58 ± 8.25 yrs, ht.=169±11 cm, and wt. = 75.4 ±14.2 kg) were tested for TBFO (Respiratory Exchange Ratio, RER) pre- and during exercise. FOwbc was not significantly different between tolerant and intolerant (0.261 ±0.078 vs. 0.296 ±0.042 nmol/h per 10⁹ wbc), or normals (0.27 ±0.09 nmol/h per 10⁹ wbc) and no common molecular abnormalities were found. Pre-exercise RER (0.73 ±0.05 vs. 0.84 ±0.05) was significantly lower in the intolerant group and the Vo ₂ at RER=1.0 (1.27 ±0.32 vs. 1.87±0.60 L/min) greater than the tolerant. Post-exercise lactates were not different between groups. Although dietary fat intake was not different, blood lipoprotein levels, particularly triglycerides were 35% lower in tolerant than previously intolerant. TBFO and blood lipoproteins were reduced in tolerant patients in spite of the absence of genetic limitations, but not in the intolerant group as hypothesized. Although not conclusive, these data suggest the need for a prospective study of the effects of statins on fat oxidation.