The genetics of prostate cancer are highly variable and not well understood. No consistent pattern of mutations across prostate cancer samples has yet been found. Due to this inherent heterogeneity it is natural to wonder whether or not using paired controls in gene expression studies might be useful. Although other studies have previously analyzed the use of paired controls for the expression of a handful of genes at a time no study has yet been performed to assess the benefits of using paired controls rather than independent controls on a large scale. By using a prostate cancer microarray data set that consisted of 58 pairs of paired cancer and control samples as well as 18 independent controls we found that searches for differentially expressed genes and for upregulated genes were significantly enhanced by using paired controls instead of independent controls.