In the complete genome sequences of Bacteroides fragilis NCTC9343 and 638R, we have discovered a gene, ubb, the product of which has 63 % identity to human ubiquitin and cross-reacts with antibodies raised against bovine ubiquitin. The sequence of ubb is closest in identity (76 %) to the ubiquitin gene from a migratory grasshopper entomopoxvirus, suggesting acquisition by inter-kingdom horizontal gene transfer. We have screened clinical isolates of B. fragilis from diverse geographical regions and found that ubb is present in some, but not all, strains. The gene is transcribed and the mRNA is translated in B. fragilis, but deletion of ubb did not have a detrimental effect on growth. BfUbb has a predicted signal sequence; both full-length and processed forms were detected in whole-cell extracts, while the processed form was found in concentrated culture supernatants. Purified recombinant BfUbb inhibited in vitro ubiquitination and was able to covalently bind the human E1 activating enzyme, suggesting it could act as a suicide substrate in vivo. B. fragilis is one of the predominant members of the normal human gastrointestinal microbiota with estimates of up to >10¹¹ cells per g faeces by culture. These data indicate that the gastro-intestinal tract of some individuals could contain a significant amount of aberrant ubiquitin with the potential to inappropriately activate the host immune system and/or interfere with eukaryotic ubiquitin activity. This discovery could have profound implications in relation to our understanding of human diseases such as inflammatory bowel and autoimmune diseases.