Invasive non-typhoidal Salmonella (iNTS) disease is a major cause of bloodstream infection and mortality among immunocompromised individuals, particularly people living with human immunodeficiency virus (HIV). Despite its clinical importance, contemporary data on the clinical characteristics, antimicrobial resistance patterns, and outcomes of iNTS disease in Vietnam remain limited. This study aims to describe the clinical features, antimicrobial susceptibility patterns, treatment outcomes, and factors associated with mortality among adults with iNTS disease in southern Vietnam. An ambispective observational study combining retrospective and prospective data collection was conducted at the Hospital for Tropical Diseases between January 2023 and December 2025. Adult patients with iNTS disease confirmed by isolation of non-typhoidal Salmonella from extraintestinal specimens were consecutively enrolled. Clinical, microbiological, treatment, and outcome data were analyzed. Among 106 patients, 74.5% were HIV-positive, and most had advanced immunosuppression with CD4 counts < 200 cells/mm 3 . Gastrointestinal manifestations were relatively uncommon, particularly among HIV-positive patients. Ampicillin (67.9%) and nalidixic acid (57.5%) showed the highest resistance rates. Resistance to ceftriaxone and ciprofloxacin remained low at 2.8% and 3.8%, respectively, while multidrug resistance was identified in 19.8% of isolates. In the exploratory multivariable analysis, respiratory failure remained strongly associated with in-hospital mortality (aPR = 9.06, 95% CI: 3.65–22.5, p < 0.001). In a sensitivity analysis adjusting for pulmonary coinfection, defined as tuberculosis and/or Pneumocystis jirovecii pneumonia, the association remained similar (aPR = 10.33, 95% CI: 4.47–23.88, p < 0.001). In this tertiary-hospital cohort in southern Vietnam, iNTS disease occurred predominantly among people living with advanced HIV infection. Although resistance to ceftriaxone and fluoroquinolones remained low, multidrug resistance was common. Respiratory failure was strongly associated with in-hospital mortality and may represent an important marker of clinical severity. However, this association should be interpreted cautiously given the limited number of deaths.
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