Zinc (Zn) is an essential trace element for all life forms. Zn supplementation has been used to treat diarrheal disease in children, and in the U.S. swine industry at pharmacological levels to promote growth and fecal consistency, but underlying mechanisms explaining these beneficial effects remain unknown. Thus, we hypothesized that the benefits of pharmacological Zn supplementation were a result of changes in gene expression. For this study, liver RNA from newly weaned pigs fed dietary Zn as Zn oxide for 14 days at either adequate (150 Zn/kg) or pharmacological (2000 mg Zn/kg) levels was evaluated using a 70-mer oligonucleotide microarray. Interrogation of this microarray revealed 658 annotated transcripts (FDR = 0.05) affected by pharmacological Zn supplementation. Relative real-time RT-PCR was used to confirm differential expression of two genes. Results suggest that feeding pharmacological Zn (2000 mg Zn/kg) affects genes involved in reducing oxidative stress and in amino acid metabolism, which are essential for cell detoxification and proper cell function. Overall design: Oligonucleotide microarrays used for this study consisted of 13,297 70-mer oligos (Pig Array-Ready Oligo Set v. 1.0 and Pig Oligo Extension Set v. 1.0, Qiagen, Inc., Valencia, CA) each spotted once on a single slide. Slides were printed at the Michigan State University Research Technology Support Facility. Oligonucleotides spotted in multiple locations for use as potential controls included 76 Arabidopsis thaliana gene spots, 17 beta tubulin spots, 17 glyceraldehyde-3-phosphate dehydrogenase spots, 85 heat shock protein gene spots, 69 ribosomal protein gene spots, 112 randomly generated negative control spots and 470 blanks. The microarray was screened with the Zn150 and Zn2000 samples, and four microarray slides were screened. Zn150 samples were randomly paired with Zn2000 samples. Two samples from each treatment were labeled with Cy3 and the other two were labeled with Cy5.