Valproic acid (VPA) is a widely used anticonvulsant and mood-stabilizing drug whose use is often associated with drug-induced weight gain. Treatment with VPA has been shown to upregulateWfs1expressionin vitro. Aim of the present study was to compare the effect of chronic VPA treatment in wild type (WT) andWfs1knockout (KO) mice on hepatic gene expression profile. Wild type,Wfs1heterozygous, and homozygous mice were treated with VPA for three months (300 mg/kg i.p. daily) and gene expression profiles in liver were evaluated using Affymetrix Mouse GeneChip 1.0 ST array. We identified 42 genes affected byWfs1genotype, 10 genes regulated by VPA treatment, and 9 genes whose regulation by VPA was dependent on genotype. Among the genes that were regulated differentially by VPA depending on genotype was peroxisome proliferator-activated receptor delta (Ppard), whose expression was upregulated in response to VPA treatment in WT, but not inWfs1KO mice. Thus, regulation ofPpardby VPA is dependent onWfs1genotype.