ABSTRACTSalmonellainfection is one of the main causes of food-borne diarrheal diseases worldwide. Although mostSalmonellainfections can be cleared without treatment, some cause serious illnesses that require antibiotic treatment. In view of the growing emergence of antibiotic-resistantSalmonellastrains, novel treatments are increasingly required. Furthermore, there is a striking paucity of data on how a balanced human gut microbiota responds toSalmonellainfection. This study aimed to evaluate whether a balanced gut microbiota protects againstSalmonellagrowth and to compare two antimicrobial approaches for managingSalmonellainfection: bacteriophage (phage) treatment and antibiotic treatment. Anaerobically cultivated human intestinal microflora (ACHIM) is a feasible model for the human gut microbiota and naturally inhibitsSalmonellainfection. By mimickingSalmonellainfectionin vitrousing ACHIM, we observed a large reduction ofSalmonellagrowth by the ACHIM itself. Treatments with phage and antibiotic further inhibitedSalmonellagrowth. However, phage treatment had less impact on the nontargeted bacteria in ACHIM than the antibiotic treatment did. Phage treatment has high specificity when combatingSalmonellainfection and offers a noninvasive alternative to antibiotic treatment.IMPORTANCEAntibiotic-resistant bacteria are a global threat. Therefore, alternative approaches for combatting bacteria, especially antibiotic-resistant bacteria, are urgently needed. Using a human gut microbiota model, we demonstrate that bacteriophages (phages) are able to substantially decrease pathogenicSalmonellawithout perturbing the microbiota. Conversely, antibiotic treatment leads to the eradication of close to all commensal bacteria, leaving only antibiotic-resistant bacteria. An unbalanced microbiota has been linked to many diseases both in the gastrointestinal tract or “nonintestinal” diseases. In our study, we show that the microbiota provides a protective effect againstSalmonella. Since phage treatment preserves the healthy gut microbiota, it is a feasible superior alternative to antibiotic treatment. Furthermore, when combating infections caused by pathogenic bacteria, gut microbiota should be considered.