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Previous studies suggested that certain lipid-lowering drugs such as statins suppress ubiquinone, affect mitochondrial function, and may have deleterious effect on skeletal or cardiac muscles with potentially serious clinical consequences, especially in patients with established coronary heart disease and left ventricular dysfunction. In this double-blind study, we assessed the effects of 20 mg simvastatin (S, n = 32) or 200 mg micronized fenofibrate (F, n = 32, control group) on rest and exercise left ventricular function in hypercholesterolemic survivors of a previous Q-wave acute myocardial infarction. Left ventricular radionuclide imaging was performed at rest and during submaximal exercise and global and segmental (nine segment regional wall-motion score) ejection fractions were measured before treatment and 12 weeks later. Serum ubiquinone was reduced after treatment (p = 0.03) in the S but not the F group, whereas total and low-density lipoprotein (LDL) cholesterol were significantly reduced in both groups. Before treatment, mean global ejection fraction was 52.1 ± 12.2% and 49.3 ± 11.8% at rest in F and S patients, respectively, and increased (56.0 ± 13.7% in F and 52.1 ± 12.9% in S) at peak exercise (no difference between groups). After treatment, the increase in ejection fraction tended to be lower in S (0) than in F (+3.8%) but not significantly. However, ejection fraction at rest increased after treatment in S (p = 0.009) but not in F. Subgroup analyses indicated that the improvement in rest ejection fraction in S was essentially observed in patients with ejection fraction <40% (n = 8, +6%), whereas it was stable in patients with ejection fraction >40% (+1.8%). Finally, the numbers of akinetic or hypokinetic segments at rest and during exercise were not different in the two groups before and after treatment. Mean maximal exercise load (113 ± 23 watts in F vs. 104 ± 27 W in S before treatment) was not modified by the treatment (111 ± 21 and 104 ± 27 W). Thus a 12-week lipid-lowering treatment with either S or F did not negatively alter left ventricular function during exercise in dyslipidemic patients with established coronary heart disease and did not affect their ability to exercise. The improvement in left ventricular function at rest after simvastatin in patients with left ventricular dysfunction warrants confirmation in further studies with large sample size.