It is well accepted that RNA viruses exist as mixed populations of genomic sequences and these quasispecies populations are relevant to viral fitness and disease. It is unclear if the same is true for DNA viruses. A candidate quasispecies DNA virus is human cytomegalovirus (HCMV), where mixed genotype infections in patients have been repeatedly demonstrated. HCMV is a betaherpesvirus and genetically, the most complex viral pathogen of humans with a ~235,000 bp dsDNA genome. To better understand this mixed genotype phenomenon, we adapted high throughput (deep) sequencing to generate genome-wide coverage of HCMV and analyze viral populations in clinical samples. We discovered that HCMV populations in the plasma, urine and saliva of patients are as diverse as many RNA viruses with standing variation ranging from 7,000-43,000 SNPs. While viral populations can evolve over time, we find that the greatest differentiation occurs during compartmentalization where viral populations in the plasma differ from secreted viral populations. I will present evidence that demography (bottlenecks/expansions) and selection are significant drivers of HCMV evolution especially during compartmentalization. Lastly, I will explore the roles of mutagenesis and reinfection as sources of HCMV genomic diversity. Our data reveal HCMV populations as diverse and dynamic and suggest that HCMV has attributes of quasispecies.