In rodents, treatment with peroxisome proliferator–activated receptor alpha (PPARα) agonists results in peroxisome proliferation, hepatocellular hypertrophy, and hepatomegaly. Drugs in the fibrate class of PPARα agonists have also been reported to produce rare skeletal muscle toxicity. Although target-driven hepatic effects of PPARα treatment have been extensively studied, a characterization of the transcriptional effects of this nuclear receptor/transcription factor on skeletal muscle responses has not been reported. In this study we investigated the effects of PPARα agonists on skeletal muscle gene transcription in rats. Further, since statins have been reported to preferentially effect type II muscle fibers, we compared PPARα signaling effects between type I and type II muscles. By comparing the transcriptional responses of agonists that signal through different nuclear receptors and using a selection/deselection analytical strategy based on ANOVA, we identified a PPARα activation signature that is evident in type I (soleus), but not type II (quadriceps femoris), skeletal muscle fibers. The fiber-type–selective nature of this response is consistent with increased fatty acid uptake and β-oxidation, which represent the major clinical benefits of the hypolipidemic compounds used in this study, but does not reveal any obvious off-target pathways that may drive adverse effects.