Here, the authors study the impact of Vibrio cholerae's T6SS on human gut microbiota isolates and show that certain bacteria are protected from T6SS attacks in an immunity protein-independent manner. Specifically, protection occurred through superior T6SS weaponry in members of the Enterobacter cloacae complex and by molecular armors made of membrane-tethered capsular polysaccharides of diverse Klebsiella isolates. While the major virulence factors for Vibrio cholerae, the cause of the devastating diarrheal disease cholera, have been extensively studied, the initial intestinal colonization of the bacterium is not well understood because non-human adult animals are refractory to its colonization. Recent studies suggest the involvement of an interbacterial killing device known as the type VI secretion system (T6SS). Here, we tested the T6SS-dependent interaction of V. cholerae with a selection of human gut commensal isolates. We show that the pathogen efficiently depleted representative genera of the Proteobacteria in vitro, while members of the Enterobacter cloacae complex and several Klebsiella species remained unaffected. We demonstrate that this resistance against T6SS assaults was mediated by the production of superior T6SS machinery or a barrier exerted by group I capsules. Collectively, our data provide new insights into immunity protein-independent T6SS resistance employed by the human microbiota and colonization resistance in general.