Development of mesothelioma is linked mainly to asbestos exposure, but the combined contributions of genetic and epigenetic alterations are unclear. We investigated the potential relationships between gene copy number (CN) alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n = 23). There were no instances of significantly correlated CN alteration and methylation at probed loci, whereas averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations. In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes. Further, there was evidence that this association was partially attributable to prevalent allele loss at the DNA methyltransferase gene DNMT1. Our findings define a strong association between global genetic and global epigenetic dysregulation in mesothelioma, rather than a discrete, local coordination of gene inactivation.