Gram-negative bacilli Vibrio spp., Aeromonas spp., and Shewanella spp. are a major cause of severe waterborne infection. The aim of this study was to assess the clinical and microbiological characteristics and prognosis of patients hospitalized in Reunion Island for a waterborne infection. This retrospective study was conducted in the two university hospitals of Reunion Island between January 2010 and March 2017. Patients diagnosed with a Vibrio, Aeromonas, or Shewanella infection were evaluated. Over the study period, 112 aquatic strains were isolated at Reunion Island: Aeromonas spp. were found in 91 patients (81.3%), Shewanella spp. in 13 patients (11.6%), and Vibrio spp. in eight patients (7.2%). The in-hospital mortality rate was 11.6%. The main sites of infection were skin and soft tissue (44.6%) and the abdomen (19.6%). Infections were polymicrobial in 70 cases (62.5%). The most commonly prescribed empiric antibiotic regimen was amoxicillin-clavulanate (34.8%). Eighty-four percent of the aquatic strains were resistant to amoxicillin-clavulanate and more than > 95% were susceptible to third or fourth generation cephalosporins and fluoroquinolones. After multivariate analysis, the only independent risk factor of in-hospital mortality was the presence of sepsis (P < 0.0001). In Reunion Island, the most commonly isolated aquatic microorganisms were Aeromonas spp. Sepsis caused by aquatic microorganisms was frequent (> 50%) and associated with higher in-hospital mortality. This study suggests that empiric antibiotic regimens in patients with sepsis or septic shock caused by suspected aquatic microorganisms (tropical climate, skin lesion exposed to seawater…) should include broad-spectrum antibiotics (third or fourth generation cephalosporins).