Hypertrophic scars cause cosmetic disfigurement and limited mobility in burn patients. To better understand the molecular pathophysiology of hypertrophic scar formation, microarray analyses were performed on normal skin and hypertrophic scars from four burn patients. Microarray analyses were determined in an effort to identify genes whose expression discriminated between normal skin and mature, hypertrophic scars. Surgical biopsies were obtained from two pediatric and two adult patients 6 to 15 months after burn injury. Total RNA was isolated from the samples and subjected to microarray analysis using the Affymetrix U95Av2 GeneChip®. Results from this analysis revealed 31 probe sets representing genes that were consistently up-regulated at least two-fold in hypertrophic scar specimens from all four patients and four probe sets that were down-regulated. The significance analysis of microarrays algorithm also identified 35 probe sets whose increased expression resulted in the hierarchal clustering of the hypertrophic scar and normal tissue, seven of which were identical to the six genes identified by paired analyses. These six genes all displayed elevated levels of expression in the scar tissue. Proteins encoded by the genes identified included germline oligometric matrix protein, matrix metalloproteinase-16, collagen type 1α, pleiotrophin, and thrombospondin-4. Although the results presented here suggest that there may be unique patterns of gene expression in hypertrophic scars that may be important in the evaluation and treatment of hypertrophic scarring, the results must be confirmed with larger datasets.