Sinclair swine develop an aggressive form of melanoma, which, in many cases, spontaneously regresses after a complete metastatic phase. We used Affymetrix GeneChip® Porcine Genome Arrays consisting of 24 123 probe sets to compare gene expression in white blood cells (WBCs) and various tissues including the liver, lungs, inguinal lymph nodes and spleen harvested from a Sinclair piglet afflicted by melanoma at birth and exhibiting metastatic lesions at weaning (6 weeks) with those from a full-sibling piglet that showed no incidence of melanoma at birth and weaning. The highest number (3489; ∼14%) of significantly upregulated transcripts (fold change in gene expression ≥2.0 and t-test P-value ≤0.05) was observed in the liver, while the spleen exhibited the lowest number of upregulated transcripts (528; ∼2%). Among significantly downregulated genes, the highest numbers were observed in the inguinal lymph nodes (3651; ∼15%) and the least in WBCs (730; ∼3%). Differentially expressed transcripts included genes involved in melanoma pathogenesis including SILV, TYR and RAB28. SILV was over-expressed 784-, 430- and 164-fold, while TYR was over-expressed 138-, 81- and 28-fold in the liver, lungs and inguinal lymph nodes, respectively. Quantitative real-time RT-PCR (qRT-PCR) confirmed the microarray data of 12 selected differentially expressed sequences. These results suggest that significant changes in gene expression occur during metastasis of malignant melanoma in the Sinclair swine model. In addition, qRT-PCR analysis of the above 12 differentially expressed sequences was carried out on liver samples collected from 22 pigs (12 of which had melanoma during the first 6 weeks of life), and an ANOVA test contrasting absolute RNA expression between pigs with regressing, progressing and without tumors was significant for TYR, TACSTD1, MATP, GPNMB and CYP4A22, with P-values of 0.034, 0.015, 0.007, 0.050 and 0.022, respectively.