Burkholderia glumae causes rice (Oryza sativa) bacterial panicle blight, which is an increasingly economically important disease worldwide. As the first B. glumae strain isolated from patients with chronic infections, AU6208 has been reported as an opportunistic clinic pathogen. However, our understanding of the molecular mechanism underlying human pathogenesis by B. glumae remains rudimentary. In this study, we report the complete genome sequence of the human-isolated B. glumae strain AU6208 and compare this to the genome of the rice-pathogenic B. glumae type strain LMG 2196T. Analysis of the average nucleotide identity demonstrated 99.4% similarity between the human- and plant-pathogenic strains. However, the phenotypic results from this study suggest a history of niche adaptation and divergence. In particular, we found 44 genes were predicted to be horizontally transferred into AU6208, and most of these genes were upregulated in conditions that mimic clinical conditions. In these, the gene pair sbnAB encodes key enzymes in antibiotic biosynthesis. These results suggest that horizontal gene transfer in AU6208 may be responsible for selective advantages in its pathogenicity in humans. Our analysis of the AU6208 genome and comparison with that of LMG 2196T reveal the evolutionary signatures of B. glumae in the process of switching niches from plants to humans.