Therapeutic use of certain peroxisome proliferator–activated receptor (PPAR) alpha agonists (fibrates) for the treatment of dyslipidemia has infrequently been associated with the untoward side effect of myopathy. With interest in PPAR-δ as a therapeutic target, this study assessed whether a PPAR-δ agonist induced similar hepatic and skeletal muscle alterations as noted with some fibrates. PPAR-α null (KO) and corresponding wild-type (WT) mice were administered toxicological dosages of a potent PPAR-δ agonist tool ligand (GW0742; which also has weak PPAR-α agonist activity) or a potent PPAR-α agonist (WY-14,643) for 10 days. Increases in liver weights and clinical chemistry indicators of skeletal muscle damage and/or liver injury were more pronounced in WT mice compared with KO mice administered the PPAR-δ agonist. Likewise, the incidence and severity of skeletal myopathy were greater in WT mice given GW0742 compared with KO mice. Ultrastructural and immunohistochemical analyses revealed significant peroxisome proliferation in muscle and liver of WT mice treated with each agonist; however, KO animals showed little or no evidence of hepatic and muscle peroxisome proliferation. PMP-70 protein expression in liver was consistent with these results. The hepatomegaly, hepatic and skeletal muscle peroxisome proliferation, and skeletal myopathy induced by this PPAR-δ ligand was predominantly mediated by its cross-activation of PPAR-α, though PPAR-δ agonism contributed slightly to these effects.