| Summary: | <i>Lawsonia intracellularis</i> infections are a common reason for antibiotic treatment in pig production. Experimental studies in animals naturally infected with <i>Lawsonia intracellularis</i> comparing the course of an experimental <i>Salmonella</i> infection in piglets previously treated with tylosin or vaccinated against <i>Lawsonia intracellularis</i> are scarce. A total of 72 seven-week-old <i>Salmonella</i>-free pigs were taken from a herd with a <i>Lawsonia intracellularis</i> history in piglet rearing. The pigs were divided into two groups with three replicates each. Animals had either been previously treated with tylosin (10 mg/kg body weight) for seven days (AB<sup>+</sup>VAC<sup>−</sup>) or had been vaccinated as suckling pigs by drenching (Enterisol<sup>®</sup>Ileitis; AB<sup>−</sup>VAC<sup>+</sup>). Two animals per replicate were primarily infected with <i>Salmonella</i> Derby (1.04 × 10<sup>8</sup> colony-forming units per animal). The detection of <i>Salmonella</i> in faeces (<i>p</i> < 0.0001, odds ratio: 3.8364) and in the ileocaecal lymph nodes (<i>p</i> = 0.0295, odds ratio: 3.5043) was significantly more frequent in AB<sup>+</sup>VAC<sup>−</sup> animals. Overall, the odds ratio for detecting <i>Salmonella</i> in any substrate or organ was significantly higher in the AB<sup>+</sup>VAC<sup>−</sup> group animals (<i>p</i> = 0.0004, odds ratio: 5.9091). Treatment with tylosin can significantly increase the spread of a <i>Salmonella</i> infection, which is not observed after early <i>Lawsonia intracellularis</i> vaccination.
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